COMT inhibiting methods and compositions

ABSTRACT

The present inventions include a method of inhibiting COMT enzyme in a subject as well as compounds of formula I, or a pharmaceutically acceptable salt thereof, that are useful in the treatment of various disorders mediated by COMT, including Parkinson&#39;s disease and/or schizophrenia.

FIELD OF THE INVENTION

This invention relates to compounds, pharmaceutical compositions andtheir use for treating neuropsychiatric and neurodenerative disorders.In particular, the invention relates to inhibitors ofcatechol-O-methyltransferase and their use as therapeutics for centralnervous system disease.

BACKGROUND

Cognitive disorders are observed in many neurological and psychiatricdisorders, be they neurodegenerative (e.g. Parkinson's disease,Alzheimer's disease), neurodevelopmental (e.g. schizophrenia, autismspectrum disorders) or the consequence of other etiology.

Parkinson's disease is a progressive neurodegenerative disorder(synucleopathy) diagnosed on the basis of characteristic motordisturbances, asymmetry of symptoms onset and response to levodopa(Litvan et al., 2003). Lewy bodies, neurofibrillary tangles and plaquesare observed in nigral, limbic and neocortical regions. Thesedegenerations are supposed to affect catecholaminergic (dopamine andnorepinephrine) and cholinergic neurotransmission. In particular, animportant part of cognitive deficits (executive function and workingmemory) have been related to a decreased prefrontal dopaminergicsignalling in non demented patients (Nandakumar et al., 2013).

Schizophrenia is the result of a complex series of neurodevelopmental orother changes that lead to impaired information processing in the brain(Marenco and Weinberger 2000). No single genetic change, aberrantprotein function, or visible brain lesion has been demonstrated to leadto schizophrenia, and many different genetic and environmental changesare linked to increased disease risk (Fatemi and Folsom 2009). Whilemany neurochemical signaling systems, such as the various monoamines,NMDA, and GABA, are likely to play a role in the etiology ofschizophrenia (Pickard 2011), many pathways seem to converge on aberrantdopamine signaling as a final common pathway that leads to many of theobserved symptoms (Howes and Kapur 2009).

With regard to the cognitive impairment, for which there is currently notreatment, patients with schizophrenia show significant deficits inspecific cognitive domains, especially executive function, workingmemory, and episodic memory. Cognitive domains which are dysfunctioningin these two disorders are complex functions involving manyneurotransmitters and brain regions; however, dopamine signaling in thedorsolateral prefrontal cortex (DLPFC) has been shown to play a criticalrole in these processes (Goldman-Rakic, Castner et al. 2004). Oneapproach to rectifying cortical dopamine neurotransmission is to takeadvantage of the differential modes of clearance of dopamine from thedifferent brain regions. In the midbrain, there is extensive expressionof the dopamine transporter (DAT), which is thought to be primarilyresponsible for dopamine clearance from the synapse (Ciliax, Heilman etal. 1995). In contrast, cortical regions exhibit only low levels of DATexpression, and dopamine is cleared primarily by enzymatic catabolism ofdopamine, with a contribution from the norepinephrine transporter (NET)(Yavich, Forsberg et al. 2007; Kaenmaki, Tammimaki et al. 2010). Theprimary enzymes responsible for dopamine catabolism in the prefrontalcortex (“PFC”) are monoamine oxidase (MAO) andcatechol-O-methyltransferase (“COMT”).

Beyond Parkinson's and schizophrenia, inhibition of COMT may be usefulin a number of neuro-psychiatric conditions, including ADHD,obsessive-compulsive disorder, alcoholism, depression, bipolar disorder(Lachman, Papolos et al. 1996), as well as age-associated cognitivesymptoms, impulse control disorders, including compulsive gambling,sexual behavior, and other compulsive destructive behaviors. The role ofCOMT in dopamine metabolism in the brain make it an especially importanttarget for improvement of cognition (Apud and Weinberger 2007).

Additionally, COMT inhibitors have shown utility in Parkinson's diseasetreatment, due to the role of COMT in metabolizing the dopamineprecursor L-DOPA, which is given to Parkinson's disease patients toboost the levels of dopamine in the brain (Bonifacio, Palma et al.2007). Since dopamine cannot cross the blood-brain barrier, L-DOPA isadministered in its place and is transported into the brain andsubsequently processed to dopamine. The percentage of exogenouslyadministered L-DOPA that reaches the brain is ˜1%, and this low brainavailability necessitates a high dose, which leads to peripheral sideeffects (Nutt and Fellman 1984). The primary enzymes responsible fordopamine metabolism are aromatic amino acid decarboxylase (AAAD) andCOMT. Therefore, extensive efforts have been undertaken to developpotent and selective inhibitors of both enzymes. Carbidopa is an AAADinhibitor now routinely given with L-DOPA, reducing the efficaciousL-DOPA dose by 60-80% (Nutt, Woodward et al. 1985). Addition of a COMTinhibitor further decreases the variability of L-DOPA exposure, and abrain-penetrating COMT inhibitor could also increase brain dopaminelevels.

Inhibitors of COMT have been developed for treatment of Parkinson'sdisease (Learmonth, Kiss et al. 2010). Notably, the nitrocatecholscaffold has been exploited to provide the clinically used drugstolcapone and entacapone (Bonifacio, Palma et al. 2007). While they areeffective in blocking peripheral COMT activity, entacapone hasnegligible brain penetration, and tolcapone has low but measurablelevels in the brain (Russ, et al. 1999). Compounds with improved brainpenetration should have greater efficacy for Parkinson's disease, aswell as have utility for other psychiatric and neurological conditionssuch as cognitive impairment in schizophrenia. Despite the earlyclinical success achieved with tolcapone, the drug has been associatedwith serious liver injury, including three deaths, and requires strictliver function monitoring (Olanow and Watkins 2007). Thus, therisk-benefit profile for tolcapone prevents its widespread deployment,and new, inhibitors of COMT are needed, especially those that are activein the brain. Borchardt disclosed a series of non-nitrocatecholquinoline COMT inhibitors, but these compounds had weak potency(Borchardt, Thakker et al. 1976).

Accordingly, there remains a need for potent inhibitors of COMT andmethods of using the same to treat central nervous system disorders.

SUMMARY OF THE INVENTION

The present invention provides compounds, pharmaceutical compositionsand methods of treating or preventing neurological or psychiatricdisorders for which inhibiting COMT provides a therapeutic effect.

The present invention also provides methods of treating or preventing aneurological or psychiatric disorder, or treating symptoms associatedwith a neurological or psychiatric disorder, and in particular suchdisorders for which inhibiting COMT provides a therapeutic effect. In aparticular embodiment, the invention provides a method of inhibitingCOMT enzyme in a subject by administering compounds according to formulaI, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;Z is selected from SO₂R¹ and SO₂NR²R³;R¹ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl and heteroarylalkyl, any of which may besubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino,oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl,CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄alkyl or (R⁴)₂ forms a carbocyclic ring;R² and R³ are independently selected from hydrogen and any of the groupsas defined for R¹, with the proviso that at least one of R² or R³ isdifferent from hydrogen; or R² and R³ may together form a 3-10 memberedmonocyclic, bicyclic or spirocyclic nitrogen-containing ring system thatcontains 0-3 (preferably 0-1) additional heteroatoms selected fromoxygen (O), nitrogen (N), and sulfur (S), and which may be furthersubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino,C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl,aralkyl, heterocyclyl, heteroaryl or heteroarylalkyl;with the proviso that when X is hydrogen and Z is SO₂R¹, R¹ is not C₄alkyl, C₈ alkyl, tetrahydropyran or propylcyclopropane;or when X is H and Z is SO₂NR²R³, R² and R³ do not together form a1-piperidinyl ring substituted with a ca-methyl group;or when X is Cl and Z is SO₂R¹, R¹ is not C₃ alkyl, C₄ alkyl or C₅-C₆cycloalkyl;or when X is Cl and Z is SO₂NR²R³, R² and R³ do not together form anunsubstituted, 1-pyrrolidinyl ring;

A further embodiment of the above includes the additional proviso thatwhen X is F and Z is SO₂R¹, R¹ is not pyridyl, cyclopentyl, or phenylsubstituted with fluoro or trifluoromethyl.

A second additional embodiment of the above further includes the provisothat when X is Cl and Z is SO₂R¹, R¹ is not thiazolyl, pyridyl,pyridyl-N-oxide, and phenyl substituted with one or two groups selectedfrom fluoro, chloro, methyl, trifluoromethyl, phenyl and tert-butyl.

Also provided herein are COMT-inhibiting compounds in accordance withformula I, or pharmaceutically acceptable salts thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;Z is selected from SO₂R¹ and SO₂NR²R³;R¹ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl and heteroarylalkyl, any of which may besubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino,oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl,CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄alkyl or (R⁴)₂ forms a carbocyclic ring;R² and R³ are independently selected from hydrogen and any of the groupsas defined for R¹, with the proviso that at least one of R² or R³ isdifferent from hydrogen; or R² and R³ may together form a 3-10 memberedmonocyclic, bicyclic or spirocyclic nitrogen-containing ring system thatcontains 0-3 (preferably 0-1) additional heteroatoms selected fromoxygen (O), nitrogen (N), and sulfur (S), and which may be furthersubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino,C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl,aralkyl, heterocyclyl, heteroaryl or heteroarylalkyl;with the proviso that when X is hydrogen and Z is SO₂R¹, R¹ is not C₁alkyl, C₄ alkyl, C₈ alkyl, phenyl, 4-methyphenyl, 4-methoxybenzyl,4-bromophenyl, 4-iodophenyl, 2,4,6-trimethylphenyl, CH(COMe)₂,CH(CO₂Et)₂, 4-BnOPh, tetrahydropyran or propylcyclopropane; or when X isH and Z is SO₂NR²R³, R² and R³ do not together form a 1-piperidinyl ringsubstituted with a ca-methyl group;or when X is Cl and Z is SO₂R¹, R¹ is not C₃ alkyl, C₄ alkyl or C₅-C₆cycloalkyl;or when X is Cl and Z is SO₂NR²R³, R² and R³ do not together form anunsubstituted, 1-pyrrolidinyl ring.

An additional embodiment of the above includes the proviso that when Xis F and Z is SO₂R¹, R¹ is not pyridyl, cyclopentyl and phenylsubstituted with fluoro, or trifluoromethyl.

A second additional embodiment of the above further includes the provisothat when X is Cl and Z is SO₂R¹, R¹ is not thiazolyl, pyridyl,pyridyl-N-oxide, and phenyl substituted with one or two groups selectedfrom fluoro, chloro, methyl, trifluoromethyl, phenyl and tert-butyl.

Also provided herein are pharmaceutical compositions comprising theCOMT-inhibiting compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The terms below, when used herein, have the following meanings unlessindicated otherwise.

As used in this specification and the appended claims, the singularforms “a”, “an” and “the” include plural references unless the contentclearly dictates otherwise.

When any variable (e.g. aryl, heterocycle, R¹, etc.) occurs more thanone time in any constituent, its definition on each occurrence isindependent at every other occurrence.

“Alkyl” refers to a saturated hydrocarbon chain, in certain embodimentsranging from about 1 to 20 carbon atoms in length, in other embodimentsabout 1 to 12 carbon atoms in length. Such hydrocarbon chains may bebranched or linear. “Alkyl” groups may be substituted by one or moresubstituents selected from halogen, amido, aryl or alkoxy. Particularalkyl groups according to the present invention include methyl,trifluoromethyl, ethyl, propyl, butyl, pentyl, 1-methylbutyl,1-ethylpropyl, 3-methylpentyl, octyl and the like.

The term “C₁-C₆” (for example), or “C₁-6”, includes, for this example,alkyls containing 6, 5, 4, 3, 2, or 1 carbon atom(s).

“Lower alkyl” refers to an alkyl group containing from 1 to 6 carbonatoms, preferably 1 to 4 carbon atoms, and may be linear or branched, asexemplified by methyl, ethyl, isopropyl, isobutyl, n-butyl, and t-butyl.C₁-C₄ alkyl refers to an alkyl group containing 1 to 4 carbon atoms.

As used herein, “haloalkyl” refers to an alkyl group as described hereincontaining at least one halogen substituent. One particular exampleaccording to the invention is trifluoromethyl.

“Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarbonradical, including bridged, fused, or spiro cyclic compounds, preferablyhaving 3 to about 10 or 12 carbon atoms, more preferably 3 to about 8.Nonlimiting examples of “C₃-C₆ cycloalkyl” groups according to thepresent invention are cyclopropyl, cyclopentyl, cyclohexyl and the like.

As used herein, “alkenyl” refers to a branched or unbranched hydrocarbonhaving t least one carbon-carbon double bond, and is preferably about 2to about 15 carbon atoms and containing at least one double bond, suchas ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl,decenyl, tetradecenyl, and the like. C₂-C₄ alkenyl refers to an alkenylgroup containing 2 to 4 carbon atoms.

The term “alkynyl” as used herein refers to a branched or unbranchedhydrocarbon having at least one carbon-carbon triple bond, and ispreferably about 2 to about 15 carbon atoms and containing at least onetriple bond, such as ethynyl, n-propynyl and the like.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. The “aryl” groups may be unsubstituted orsubstituted by 1 to 3 substituent independently selected from C₁-C₄alkyl, C₁-C₄ alkoxy, halogen, cyano, amido, hydroxy, aryl orheterocycle. Nonlimiting examples of such aryl elements include phenyl,fluorophenyl, chlorophenyl, methylphenyl, dichlorophenyl, naphthyl,tetrahydronaphthyl, indanyl, biphenyl and the like.

“Aralkyl” refers to an alkyl group having an aryl substituent as definedhereabove. Nonlimiting examples of aralkyl groups according to thepresent invention are benzyl, 2-chlorobenzyl, 2,3-dichlorobenzyl,4-fluorobenzyl, 4-methylbenzyl, (4-methylphenyl)ethyl and the like.

“Amino” refers to the group —NH_(2′).

“C₁-C₄ alkylamino” refers to the group —NRR′ wherein one of R, R′ ishydrogen or “C₁-C₄ alkyl”, and the other is C₁-C₄ alkyl.

“Acyl” refers to the group —C(═O)R where R is “C₁-C₆ alkyl”, “C₂-C₆alkenyl”, “C₂-C₆ alkynyl”, “C₃-C₈ cycloalkyl”, “heterocycloalkyl”,“aryl” or “heteroaryl”. A nonlimiting example of an acyl group accordingto the present invention is acetyl, 2,3-dichlorobenzoyl and the like.

“Alkoxy” refers to the group —OR where R includes “C₁-C₆ alkyl”, “C₃-C₈cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, “aralkyl” or“heteroarylalkyl”. C₁-C₄ alkoxy refers to the group —OR where R is aC₁-C₄ alkyl group, Aryloxy refers to the group —OR where R is an arylgroup. Arylalkoxy refers to the group —OR where R is an aralkyl group.

“Alkoxycarbonyl” refers to the group —C(O)OR where R includes“C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”.

The term heterocycle, heterocyclyl, or heterocyclic, as used herein,represents a stable 5- to 7-membered monocyclic or stable 8- to11-membered bicyclic heterocyclic ring which is either saturated orunsaturated, and which consists of carbon atoms and from one to fourheteroatoms selected from the group consisting of N, O, and S, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring maybe attached at any heteroatom or carbon atom which results in thecreation of a stable structure. In certain embodiments, the heteroatomsare selected from O and N.

The term “heterocycle” or “heterocyclic” includes heteroaryl moieties.Nonlimiting examples of such heterocyclic elements include, but are notlimited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl,benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl,imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl,isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl,morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl,piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, tetrahydrofuryl, tetrahydro isoquinolinyl,tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl andtriazolyl.

In certain embodiments, the heterocyclic group is a heteroaryl group. Asused herein, the term “heteroaryl” refers to groups having 5 to 14 ringatoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 [pi]electrons shared in a cyclic array; and having, in addition to carbonatoms, between one and about three heteroatoms selected from the groupconsisting of N, O, and S which may be saturated, such as piperidinyl,partially saturated, or unsaturated, such as pyridinyl, and wherein thenitrogen and sulfur heteroatoms may optionally be oxidized, and thenitrogen heteroatom may optionally be quaternized, and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure. Examples of such heteroaryl groups include, but are notlimited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran,benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline,cinnoline, furan, furazan, imidazole, indazole, indole, indolizine,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline,quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine,triazole, and N-oxides thereof.

In certain other embodiments, the heterocyclic group is fused to an arylor heteroaryl group. Examples of such fused heterocycles include,without limitation, tetrahydroquinolinyl and dihydrobenzofuranyl.Examples of heterocycloalkyls include, without limitation, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

The term “heteroatom” means O, S or N, selected on an independent basis.

“Halogen” and “halo” refer to fluorine, chlorine, bromine and iodine.

A moiety that is “substituted” is one in which one or more hydrogenshave been independently replaced with another chemical substituent.Suitable substituents include, without limitation, halogen, hydroxy, oxo(e.g., an annular—CH— substituted with oxo is —C(═O)—), nitro,halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino,acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy,hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido,arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, andureido groups.

Other possible substituents, which are themselves not furthersubstituted (unless expressly stated otherwise) are: (a) halo, cyano,oxo, carboxy, formyl, nitro, amino, amidino, and guanidino, and (b)C₁-C₆ alkyl or alkenyl or arylalkyl imino, carbamoyl, azido,carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl,C₁-C₈ alkyl, SO₂CF₃, CF₃, SO₂Me, C₁-C₈ alkenyl, C₁-C₈ alkoxy, C₁-C₈alkoxycarbonyl, aryloxycarbonyl, C₂-C₈ acyl, C₂-C₈ acylamino, C₁-C₈alkylthio, arylalkylthio, arylthio, C₁-C₈ alkylsulfinyl,arylalkylsulfinyl, arylsulfinyl, C₁-C₈ alkylsulfonyl, arylalkylsulfonyl,arylsulfonyl, C₂-C₁₅ N,N-alkylcarbamoyl, C₂-C₁₅ N,N-dialkylcarbamoyl,C₃-C₇ cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to acycloalkyl or heterocycle or another aryl ring, C₃-C₇ heterocycle, orany of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl,or aryl, wherein each of the foregoing in (b) can be further substitutedwith one more moieties listed in (a), above. Each instance of C₈ notedin this paragraph may be, in further embodiments, C₆.

Compounds described herein may contain one or more double bonds and maythus give rise to cis/trans isomers as well as other conformationalisomers. The present invention includes all such possible isomers aswell as mixtures of such isomers unless specifically stated otherwise.

The compounds of the present invention may contain one or moreasymmetric centers and may thus occur as racemates, racemic mixtures,single enantiomers, diastereomeric mixtures, and individualdiastereomers.

It will be understood that, as used herein, references to the compoundsof the present invention are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds or inother synthetic manipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salts” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids. When the compound of the presentinvention is acidic, its corresponding salt can be conveniently preparedfrom pharmaceutically acceptable non-toxic bases, including inorganicbases and organic bases. Salts derived from such inorganic bases includealuminum, ammonium, calcium, copper (ic and ous), ferric, ferrous,lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc andthe like salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, as well as cyclic amines and substituted amines such asnaturally occurring and synthesized substituted amines. Otherpharmaceutically acceptable organic non-toxic bases from which salts canbe formed include ion exchange resins such as, for example, arginine,betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamme, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, and tromethamine.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.

A “pharmaceutically acceptable excipient” or “pharmaceuticallyacceptable carrier” refers to an excipient that can be included in thecompositions of the invention and that causes no significant adversetoxicological effects to the subject or patient to which the compositionis administered. “Pharmacologically effective amount,” “physiologicallyeffective amount,” and “therapeutically effective amount” are usedinterchangeably herein to mean the amount of an active agent present ina pharmaceutical preparation that is needed to provide a desired levelof active agent and/or conjugate in the bloodstream or in the targettissue. The precise amount will depend upon numerous factors, e.g., theparticular active agent, the components and physical characteristics ofpharmaceutical preparation, intended patient population, patientconsiderations, and the like, and can readily be determined by oneskilled in the art, based upon the information provided herein andavailable in the relevant literature.

The term “patient” refers to a living organism suffering from or proneto a condition that can be prevented or treated by administration of anactive agent as described herein, and includes both humans and animals.In one embodiment, the patient is a human patient.

The term “mammal” “mammalian” or “mammals” includes humans, as well asanimals, such as dogs, cats, horses, pigs and cattle.

Without being bound by theory, the administration of compounds accordingto the invention in an “effective amount” or “therapeutically effectiveamount” provides a concentration of the compound that functions as aCOMT inhibitor sufficient to inhibit the effect of the COMT enzymecomplex.

“Treating” or “treatment” of a disease state includes: 1) inhibiting thedisease state, i.e., arresting the development of the disease state orits clinical symptoms; 2) attenuating the disease state, i.e. reducingthe number or intensity of one or more symptoms associated with thedisease state, such that one or more symptoms is reduced but may, or maynot be completely eliminated; and/or 3) relieving the disease state,i.e., causing temporary or permanent regression of the disease state orits clinical symptoms.

“Prevent” or “preventing” a disease state includes: preventing thedisease state, i.e. causing the clinical symptoms of the disease statenot to develop in a subject that may be exposed to or predisposed to thedisease state, but does not yet experience or display symptoms of thedisease state.

All patents, patent applications and publications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

II. Methods

One aspect of the invention is a method of treating or preventing aneurological or psychiatric disorder, or treating symptoms associatedwith a neurological or psychiatric disorder, and in particular suchdisorders for which inhibiting COMT provides a therapeutic effect.Without being bound by theory, the therapeutic effect provided accordingto the invention is achieved by inhibiting the metabolism ofcatecholamines by COMT. Accordingly, in an aspect of the invention, theinvention provides methods of treating and/or preventing disease forwhich inhibiting degradation of catecholamines such as, for example,dopamine, norepinephrine or L-dihydroxyphenylalanine (L-DOPA) provides abeneficial therapeutic effect.

In another aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering compounds of formula I. Thesemethods comprise administering to a subject in need thereof an effectiveamount of a COMT-inhibiting compound in accordance with formula I, or apharmaceutically acceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;Z is selected from SO₂R¹ and SO₂NR²R³;R¹ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl and heteroarylalkyl, any of which may besubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino,oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl,CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄alkyl or (R⁴)₂ forms a carbocyclic ring;R² and R³ are independently selected from hydrogen and any of the groupsas defined for R¹, with the proviso that at least one of R² or R³ isdifferent from hydrogen; or R² and R³ may together form a 3-10 memberedmonocyclic, bicyclic or spirocyclic nitrogen-containing ring system thatcontains 0-3 (preferably 0-1) additional heteroatoms selected fromoxygen (O), nitrogen (N), and sulfur (S), and which may be furthersubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino,C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl,aralkyl, heterocyclyl, heteroaryl or heteroarylalkyl;with the proviso that when X is hydrogen and Z is SO₂R¹, R¹ is not C₄alkyl, C₈ alkyl, tetrahydropyran or propylcyclopropane;or when X is H and Z is SO₂NR²R³, R² and R³ do not together form a1-piperidinyl ring substituted with an α-methyl group;or when X is Cl and Z is SO₂R¹, R¹ is not C₃ alkyl, C₄ alkyl or C₅-C₆cycloalkyl; or when X is Cl and Z is SO₂NR²R³, R² and R³ do not togetherform an unsubstituted, 1-pyrrolidinyl ring.

An additional embodiment of the above includes the proviso that when Xis F and Z is SO₂R¹, R¹ is not pyridyl, cyclopentyl and phenylsubstituted with fluoro, or trifluoromethyl.

A second additional embodiment of the above further includes the provisothat when X is Cl and Z is SO₂R¹, R¹ is not thiazolyl, pyridyl,pyridyl-N-oxide, and phenyl substituted with one or two groups selectedfrom fluoro, chloro, methyl, trifluoromethyl, phenyl and tert-butyl.

In particular embodiments, R¹ is selected from C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl,any of which may be substituted with one or more groups selected fromhalogen, C≡N, CF₃, OH, C₁-C₄ alkyl or alkenyl, C₁-C₄ alkoxy, aryloxy,nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₆ cycloalkyl, acyl, aryl,aralkyl, heterocyclyl or heteroaryl.

In other particular embodiments, Z is SO₂R¹ and R¹ is selected fromsubstituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstitutedC₃-C₁₀ cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl, substituted or unsubstituted C-attachedheterocyclyl, substituted or unsubstituted C-attached heteroaryl orsubstituted or unsubstituted heteroarylalkyl.

In still other particular embodiments, Z is SO₂R¹ and R¹ is selectedfrom C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, phenyl, naphthyl, aralkyl,C-attached piperidinyl, C-attached 1H-benzimidazolyl, C-attachedtetrahydro-2H-pyranyl and pyridinyl, any of which may be substitutedwith one or more groups selected from halogen, CF₃, C₁-C₄ alkyl, C₁-C₄alkoxy, C₃-C₆ cycloalkyl, substituted or unsubstituted phenyl,substituted or unsubstituted pyridinyl, substituted or unsubstitutedquinolinyl, substituted or unsubstituted 1H-indazolyl, substituted orunsubstituted aralkyl or acyl. Certain embodiments include the provisothat when X is fluorine and Z is SO₂R¹, R¹ is not cyclopentyl.

In further particular embodiments, when Z is SO₂NR²R³, each of R² and R³may be independently selected from hydrogen, C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl,any of which, excluding hydrogen, may be substituted with one or moregroups selected from halogen, C≡N, CF₃, C₁-C₄ alkyl or C₂-C₄ alkenyl,C₁-C₄ alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₆ cycloalkyl,aryl, aralkyl, heterocyclyl or heteroaryl; with the proviso that atleast one of R² and R³ is different from hydrogen.

In still further particular embodiments, each of R² and R³ may beindependently selected from hydrogen, C₁-C₄ alkyl, C₃-C₁₀ cycloalkyl,aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl, any ofwhich, excluding hydrogen, may be substituted with one or more groupsselected from halogen, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, amino, C₃-C₆cycloalkyl, aryl, heterocyclyl or heteroaryl.

In other particular embodiments, R² is selected from hydrogen orsubstituted or unsubstituted C₁-C₄ alkyl.

In still other particular embodiments, R³ is selected from C₁-C₄ alkyl,aryl, aralkyl, heteroaryl and heteroarylalkyl, any of which, excludinghydrogen, may be substituted with one or more groups selected fromhalogen, C₁-C₄ alkyl or C₁-C₄ alkoxy.

In further particular embodiments, when Z is SO₂NR²R³, R² and R³ maytogether form a 3-10 membered monocyclic, bicyclic or spirocyclicnitrogen-containing ring system that contains 0-3 additional heteroatomsselected from oxygen (O), nitrogen (N), and sulfur (S), and which may befurther substituted with one or more groups selected from halogen, C₁-C₄alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, arylalkoxy,nitro, amino, C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃,aryl, aralkyl, heterocyclyl, or heteroaryl.

In still further particular embodiments, the nitrogen-containing ringsystem formed by R² and R³ is a 4-7 membered monocyclic ring system or a8-10 membered bicyclic or spirocyclic nitrogen-containing ring system.In another selected embodiment the monocyclic, bicyclic or spirocyclicnitrogen-containing ring system contains 0-1 additional heteroatomsselected from oxygen (O), nitrogen (N), and sulfur (S).

In other particular embodiments, Z is SO₂NR²R³ with NR²R³ being asubstituted or unsubstituted pyrrolidinyl, substituted or unsubstitutedpiperidinyl, substituted or unsubstituted piperazinyl, substituted orunsubstituted azetidinyl, substituted or unsubstituted1,3,8-triazaspiro[4.5]decanyl, substituted or unsubstituteddihydroisoquinolinyl, substituted or unsubstituted dihydroisoindolyl,substituted or unsubstituted morpholinyl, substituted or unsubstituteddihydronaphthyridinyl or substituted or unsubstitutedazabicyclo[3.2.2]nonyl.

In still other particular embodiments, NR²R³ is a 1-pyrrolidinyl,1-piperidinyl, 1-piperazinyl, 1-azetidinyl,1,3,8-triazaspiro[4.5]dec-8-yl, 3,4-dihydro-2(1H)-isoquinolinyl,1,3-dihydro-2H-isoindol-2-yl, 4-morpholinyl,5,8-dihydronaphthyridin-7(6H)-yl, azabicyclo[3.2.2]non-3-yl which may befurther substituted with one or more groups selected from halogen, C≡N,CF₃, OH, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, arylalkoxy, amino,C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, aryl, aralkyl,heterocyclyl, or heteroaryl.

The group X in formula I, in selected embodiments, is selected fromhydrogen, halogen, trifluoromethyl, methyl and nitrile (C≡N); in furtherembodiments X in formula I is hydrogen, halogen, trifluoromethyl, ormethyl; in further embodiments of this group, said halogen is fluorineor chlorine. In one embodiment, X is fluorine. In another embodiment, Xis hydrogen. In another embodiment, X is trifluoromethyl.

In a second aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering compounds according to formula I.These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting compound in accordance withformula I, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from H, F, Br, I, C≡N, CF₃, and C₁-C₄ alkyl;Z is selected from SO₂R¹ and SO₂NR²R³;R¹ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl and heteroarylalkyl, any of which may besubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino,oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl,CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄alkyl or (R⁴)₂ forms a carbocyclic ring;R² and R³ are independently selected from hydrogen and any of the groupsas defined for R¹, with the proviso that at least one of R² or R³ isdifferent from hydrogen; or R² and R³ may together form a 3-10 memberedmonocyclic, bicyclic or spirocyclic nitrogen-containing ring system thatcontains 0-3 (preferably 0-1) additional heteroatoms selected fromoxygen (O), nitrogen (N), and sulfur (S), and which may be furthersubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino,C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl,aralkyl, heterocyclyl, heteroaryl or heteroarylalkyl;with the proviso that when X is hydrogen and Z is SO₂R¹, R¹ is not C₄alkyl, C₈ alkyl, tetrahydropyran or propylcyclopropane;or when X is H and Z is SO₂NR²R³, R² and R³ do not together form a1-piperidinyl ring substituted with an α-methyl group.

An additional embodiment of the above includes the proviso that when Xis F and Z is SO₂R¹, R¹ is not pyridyl, cyclopentyl and phenylsubstituted with fluoro, or trifluoromethyl.

A second additional embodiment of the above further includes the provisothat when X is Cl and Z is SO₂R¹, R¹ is not thiazolyl, pyridyl,pyridyl-N-oxide, and phenyl substituted with one or two groups selectedfrom fluoro, chloro, methyl, trifluoromethyl, phenyl and tert-butyl.

In a third aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering the compounds according to formulaI. These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting compound in accordance withformula I, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from halogen, C≡N, CF₃, and C₁-C₄ alkyl;Z is selected from SO₂R¹ and SO₂NR²R³;R¹ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl and heteroarylalkyl, any of which may besubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino,oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl,CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄alkyl or (R⁴)₂ forms a carbocyclic ring;R² and R³ are independently selected from hydrogen and any of the groupsas defined for R¹, with the proviso that at least one of R² or R³ isdifferent from hydrogen; or R² and R³ may together form a 3-10 memberedmonocyclic, bicyclic or spirocyclic nitrogen-containing ring system thatcontains 0-3 (preferably 0-1) additional heteroatoms selected fromoxygen (O), nitrogen (N), and sulfur (S), and which may be furthersubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino,C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl,aralkyl, heterocyclyl, heteroaryl or heteroarylalkyl;with the proviso that when X is Cl and Z is SO₂R¹, R¹ is not C₃ alkyl,C₄ alkyl or C₅-C₆ cycloalkyl;or when X is Cl and Z is SO₂NR²R³, R² and R³ do not together form anunsubstituted, 1-pyrrolidinyl ring.

An additional embodiment of the above includes the proviso that when Xis F and Z is SO₂R¹, R¹ is not pyridyl, cyclopentyl and phenylsubstituted with fluoro, or trifluoromethyl.

A second additional embodiment of the above further includes the provisothat when X is Cl and Z is SO₂R¹, R¹ is not thiazolyl, pyridyl,pyridyl-N-oxide, and phenyl substituted with one or two groups selectedfrom fluoro, chloro, methyl, trifluoromethyl, phenyl and tert-butyl.

In a specific embodiment, R¹ is ethyl, 2-propanyl, 2-methylpropyl,octyl, 3-cyclopropylpropyl, 4-methylbenzyl, 2-(4-methylphenyl)ethyl,cyclopentyl, cyclohexyl, 3-methylphenyl, 4-methylphenyl,2,4-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-tert-butylphenyl, 3-chlorophenyl,4-chlorophenyl, 4-fluorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl,4-fluoro-2-methylphenyl, 3-(quinolin-5-yl)phenyl, biphenyl-3-yl,3′-chloro-4′-fluorobiphenyl-3-yl, 3-(1H-indazol-4yl)phenyl,3-(pyridin-4-yl)phenyl, 2-naphthyl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 3-methylpyridin-4-yl, 1-(2,3-dimethylphenyl)pyridin-4-yl,4-piperidinyl, 1-(2,3-dichlorobenzoyl)piperidin-4-yl,(4-fluorobenzyl)piperidin-4-yl, 1-(4-fluorophenyl)-piperidin-4-yl,1-(2,3-dichlorobenzyl)piperidin-4-yl,1-(2-chlorobenzyl)-1H-benzimidazol-4-yl, tetrahydro-2H-pyran-4-yl.

The group X in formula I, in selected embodiments of thesulfonylquinolinol derivatives, is selected from hydrogen, halogen,methyl, trifluoromethyl, and nitrile (C≡N); in further embodiments X informula I is hydrogen, halogen or methyl; in further embodiments of thisgroup, said halogen is fluorine or chlorine. In one embodiment, X isfluorine. In another embodiment, X is hydrogen. In a further embodiment,X is trifluoromethyl.

In a fourth aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering compounds according to formula II.These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting sulfonylquinolinol derivatives inaccordance with formula II, or a pharmaceutically acceptable saltthereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;Ar is aryl or heteroaryl, optionally substituted with one or more groupsselected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl,alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀ cycloalkyl, acyl,aryl, aralkyl, heterocyclyl, heteroaryl, CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂,where each R⁴ is independently C₁-C₄ alkyl or (R⁴)₂ forms a carbocyclicring.

In particular embodiments, Ar is heteroaryl, optionally substituted withone or more groups selected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl orC₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl, CON(R⁴)₂,SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄ alkyl or (R⁴)₂forms a carbocyclic ring.

In more particular embodiments, Ar is heteroaryl selected from thefollowing moieties (arrow indicates point of attachment):

In other particular embodiments, Ar is aryl, optionally substituted withone or more groups selected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl orC₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl, CON(R⁴)₂,SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄ alkyl or (R⁴)₂forms a carbocyclic ring.

In still other particular embodiments, Ar is phenyl, optionallysubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino,oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl,CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄alkyl or (R⁴)₂ forms a carbocyclic ring.

In more particular embodiments, Ar is phenyl optionally substituted withone or more groups selected from halogen, C₁-C₄ alkyl, alkoxyl orheteroaryl.

In further particular embodiments, Ar is selected from the followingmoieties (arrow indicates point of attachment):

The group X in formula II, in selected embodiments of thesulfonylquinolinol derivatives, is selected from hydrogen, halogen,methyl, trifluoromethyl, and nitrile (C≡N); in further embodiments X informula I is hydrogen, halogen or methyl; in further embodiments of thisgroup, said halogen is fluorine or chlorine. In one embodiment, X isfluorine. In another embodiment, X is hydrogen. In a further embodiment,X is trifluoromethyl.

In a fifth aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering compounds according to formula III.These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting sulfonylquinolinol derivative inaccordance with formula III, or a pharmaceutically acceptable saltthereof:

wherein:X is selected from hydrogen, F, Br, I, C≡N, CF₃, and C₁-C₄ alkyl; andR¹ is selected from C₃-C₁₀ cycloalkyl, aryl, aralkyl, heteroaryl andheteroarylalkyl, any of which may be substituted with one or more groupsselected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl,alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀ cycloalkyl, acyl,aryl, aralkyl, heterocyclyl, heteroaryl, CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂,where each R⁴ is independently C₁-C₄ alkyl or (R⁴)₂ forms a carbocyclicring.

In particular embodiments, R¹ is selected from the following moieties(arrow indicates point of attachment):

The group X in formula III, in selected embodiments of thesulfonylquinolinol derivatives, is selected from hydrogen, halogen,methyl, trifluoromethyl, and nitrile (C≡N); in further embodiments X informula I is hydrogen, halogen or methyl; in further embodiments of thisgroup, said halogen is fluorine or chlorine. In one embodiment, X isfluorine. In another embodiment, X is hydrogen. In a further embodiment,X is trifluoromethyl.

In a sixth aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering compounds according to formula IV.These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting sulfonylquinolinol derivative inaccordance with formula IV, or a pharmaceutically acceptable saltthereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, trifluoromethyl, andC₁-C₄ alkyl; andR³ is selected from hydrogen, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl,aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or acyl, any of whichmay be substituted with one or more groups selected from halogen, C≡N,CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄alkylamino, oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl,heteroaryl, CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ isindependently C₁-C₄ alkyl or (R⁴)₂ forms a carbocyclic ring.

In more particular embodiments, X is hydrogen and R³ is selected fromaralkyl, acyl, or aryl.

In further particular embodiments, R³ is selected from the followingmoieties (arrow indicates point of attachment):

Specific sulfonylquinolinol derivatives of the present invention arethose selected from the group consisting of:

-   5-tosylquinolin-8-ol;-   5-(4-fluorophenyl)sulfonylquinolin-8-ol;-   5-(3,4-dimethylphenyl)sulfonylquinolin-8-ol;-   5-(3,5-dimethylphenyl)sulfonylquinolin-8-ol;-   5-(4-tert-butylphenyl)sulfonylquinolin-8-ol;-   5-(3-phenylphenyl)sulfonylquinolin-8-ol;-   5-(m-tolylsulfonyl)quinolin-8-ol;-   5-(3,5-dichlorophenyl)sulfonylquinolin-8-ol;-   5-(4-chlorophenyl)sulfonylquinolin-8-ol;-   5-(2,4-dimethylphenyl)sulfonylquinolin-8-ol;-   5-[4-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;-   5-(2-naphthyl sulfonyl)quinolin-8-ol;-   5-[3-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;-   5-(3-chlorophenyl)sulfonylquinolin-8-ol;-   5-(3,4-dichlorophenyl)sulfonylquinolin-8-ol;-   5-(2-pyridylsulfonyl)quinolin-8-ol;-   5-(4-pyridylsulfonyl)quinolin-8-ol;-   5-(4-methoxyphenyl)sulfonylquinolin-8-ol;-   5-(3-pyridyl sulfonyl)quinolin-8-ol;-   5-(4-fluoro-2-methyl-phenyl)sulfonylquinolin-8-ol;-   5-[2-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;-   5-(benzenesulfonyl)quinolin-8-ol;-   5-[3-(4-pyridyl)phenyl]sulfonylquinolin-8-ol;-   5-[3-(3-chloro-4-fluoro-phenyl)phenyl]sulfonylquinolin-8-ol;-   5-[3-(5-quinolyl)phenyl]sulfonylquinolin-8-ol;-   5-[3-(1H-indazol-4-yl)phenyl]sulfonylquinolin-8-ol;-   5-[(3-methyl-4-pyridyl)sulfonyl]quinolin-8-ol;-   5-[1-[(2-chlorophenyl)methyl]benzimidazol-4-yl]sulfonylquinolin-8-ol;-   5-[2-(p-tolyl)ethylsulfonyl]quinolin-8-ol;-   5-cyclohexyl sulfonylquinolin-8-ol;-   5-cyclopentylsulfonylquinolin-8-ol;-   5-(p-tolylmethylsulfonyl)quinolin-8-ol;-   5-ethyl sulfonylquinolin-8-ol;-   5-(4-piperidylsulfonyl)quinolin-8-ol;-   5-[[1-[(4-fluorophenyl)methyl]-4-piperidyl]sulfonyl]quinolin-8-ol;-   5-[[1-[(2,3-dichlorophenyl)methyl]-4-piperidyl]sulfonyl]quinolin-8-ol;-   5-[[1-(4-fluorophenyl)-4-piperidyl]sulfonyl]quinolin-8-ol;-   5-[[1-(2,3-dimethylphenyl)-4-piperidyl]sulfonyl]quinolin-8-ol;-   7-iodo-5-(p-tolyl sulfonyl)quinolin-8-ol;-   7-bromo-5-(p-tolyl sulfonyl)quinolin-8-ol;-   7-chloro-5-(p-tolyl sulfonyl)quinolin-8-ol;-   7-fluoro-5-(p-tolylsulfonyl)quinolin-8-ol;-   5-(p-tolylsulfonyl)-7-(trifluoromethyl)quinolin-8-ol; and-   5-cyclopentylsulfonyl-7-(trifluoromethyl)quinolin-8-ol.

In a seventh aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering compounds according to formula I.These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting hydroxyquinoline sulfonamidederivative in accordance with formula I, or a pharmaceuticallyacceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;Z is SO₂NR²R³, wherein NR²R³ is a 1-pyrrolidinyl, 1-piperidinyl,1-piperazinyl, 1-azetidinyl, 1,3,8-triazaspiro[4.5]dec-8-yl,3,4-dihydro-2(1H)-isoquinolinyl, 1,3-dihydro-2H-isoindol-2-yl,4-morpholinyl, 5,8-dihydronaphthyridin-7(6H)-yl,azabicyclo[3.2.2]non-3-yl which may be further substituted with one ormore groups selected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄alkenyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, arylalkoxy, nitro, amino, C₁-C₄alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl, aralkyl,heterocyclyl, or heteroaryl;with the proviso that when X is H, R² and R³ do not together form a1-piperidinyl ring substituted with a α-methyl group;or when X is Cl, R² and R³ do not together form an unsubstituted,1-pyrrolidinyl ring.

In yet another particular embodiment, the present method comprisesadministering to a subject in need thereof an effective amount of acompound of formula I, or a pharmaceutically acceptable salt thereof,wherein NR²R³ is selected from 1-pyrrolidinyl, 2-methylpyrrolidin-1-yl,(2R)-2-methylpyrrolidin-1-yl, (2S)-2-methylpyrrolidin-1-yl,(3R,4R)-3,4-difluoropyrrolidin-1-yl, 2-(propan-2-yl)pyrrolidin-1-yl,2-(2-methylpropyl)pyrrolidin-1-yl, 2-cyclohexylpyrrolidin-1-yl,2-benzylpyrrolidin-1-yl, 2-phenylpyrrolidin-1-yl,2-(2-methylphenyl)pyrrolidin-1-yl, 2-(4-fluorophenyl)pyrrolidin-1-yl,3-(4-fluorophenyl)pyrrolidin-1-yl, 2-(4-methoxyphenyl)pyrrolidin-1-yl,2-[2-(trifluoromethyl)phenyl]pyrrolidin-1-yl,2-(pyridin-2-yl)pyrrolidin-1-yl, 2-(pyridin-3-yl)pyrrolidin-1-yl,2-(pyridin-4-yl)pyrrolidin-1-yl, 1-piperidinyl, 2-phenylpiperidin-1-yl,3-phenylpiperidin-1-yl, 4-phenylpiperidin-1-yl,4-hydroxy-4-phenylpiperidin-1-yl, 4-acetyl-4-phenylpiperidin-1-yl,4-benzylpiperidin-1-yl, 4-benzoylpiperidin-1-yl, 1-piperazinyl,2-methylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-phenylpiperazin-1-yl,4-(2,3-dimethylphenyl)piperazin-1-yl,4-(2,5-dimethylphenyl)piperazin-1-yl, 4-(4-fluorophenyl)piperazin-1-yl,4-(2,3-dichlorophenyl)piperazin-1-yl,4-[4-(trifluoromethyl)phenyl]piperazin-1-yl,4-(2-cyanophenyl)piperazin-1-yl, 4-(biphenyl-2-yl)piperazin-1-yl,4-benzylpiperazin-1-yl, 4-(4-fluorobenzyl)piperazin-1-yl,4-(3-methoxypropyl)piperazin-1-yl, 4-(methoxycarbonyl)piperazin-1-yl,4-(tert-butoxycarbonyl)piperazin-1-yl,4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl,4-(5-chloropyridin-2-yl)piperazin-1-yl,4-[bis(4-fluorophenyl)methyl]piperazin-1-yl,4-(1,2-benzothiazol-3-yl)piperazin-1-yl,3,4-dihydroisoquinolin-2(1H)-yl, 1,3-dihydro-2H-isoindol-2-yl,5,8-dihydro-1,7-naphthyridin-7(6H)-yl,4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl or3-azabicyclo[3.2.2]non-3-yl,3-[4-(trifluoromethoxy)phenoxy]azetidin-1-yl.

The present method comprises administering to a subject in need thereofan effective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof, wherein X is selected from hydrogen, halogen,and nitrile (C≡N); in further embodiments X in formula I is hydrogen,halogen or methyl; in further embodiments of this group, said halogen isfluorine or chlorine. In one embodiment, X is fluorine. In anotherembodiment, X is hydrogen.

In an eighth aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering compounds according to formula V.These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting hydroxyquinoline sulfonamidederivative in accordance with formula V, or a pharmaceuticallyacceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;R² and R³ are independently selected from hydrogen, C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl,any of which may be substituted with one or more groups selected fromhalogen, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro,amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl,heterocyclyl, heteroaryl, CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴is independently C₁-C₄ alkyl or (R⁴)₂ forms a carbocyclic ring.

In particular embodiments, NR²R³ is selected from the following moieties(arrow indicates point of attachment):

In a ninth aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering compounds according to formula VI.These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting hydroxyquinoline sulfonamidederivative in accordance with formula VI, or a pharmaceuticallyacceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;R⁵, R^(5′), R⁶, R^(6′), R⁷ and R^(7′) are each independently selectedfrom hydrogen, halogen, hydroxyl, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino, C₁-C₄ alkoxycarbonyl,acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl, aralkyl, heterocyclyl,heteroaryl or heteroarylalkyl, ortwo of R⁵, R^(5′), R⁶, R^(6′), R⁷ and R^(7′) come together to form analiphatic or aromatic ring; with the proviso that when X is H, neitherR⁶ nor R^(6′) are a methyl group.

In particular embodiments, the piperidine with R⁵, R^(5′), R⁶, R^(6′),R⁷ and R^(7′) substitution is selected from the following moieties(arrow indicates point of attachment):

In a tenth aspect, the invention provides a method of inhibiting COMTenzyme in a subject by administering compounds according to formula VII.These methods comprise administering to a subject in need thereof aneffective amount of a COMT-inhibiting hydroxyquinoline sulfonamidederivatives in accordance with formula VII, or a pharmaceuticallyacceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;R³, R⁵, R^(5′), R⁶ and R^(6′) are each independently selected fromhydrogen, halogen, hydroxyl, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl,C₃-C₆ cycloalkyl, alkoxy, nitro, amino, C₁-C₄ alkoxycarbonyl, acyl,C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl, aralkyl, heterocyclyl, heteroarylor heteroarylalkyl, ortwo of R³, R⁵, R^(5′), R⁶ or R^(6′) come together to form an aliphaticor aromatic ring.

In particular embodiments, R⁵, R^(5′), R⁶ and R^(6′) are each hydrogen.

In other particular embodiments, the piperizine with R³, R⁵, R^(5′), R⁶and R^(6′) substitution is selected from the following moieties (arrowindicates point of attachment):

In an eleventh aspect, the invention provides a method of inhibitingCOMT enzyme in a subject by administering compounds according to formulaVIII. These methods comprise administering to a subject in need thereofan effective amount of a COMT-inhibiting hydroxyquinoline sulfonamidederivatives in accordance with formula VIII, or a pharmaceuticallyacceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;R³, R^(3′), R⁴, R^(4′), R⁵, R^(5′), R⁶ and R^(6′) are each independentlyselected from hydrogen, halogen, hydroxyl, C≡N, CF₃, OH, C₁-C₄ alkyl orC₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino, C₁-C₄alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl, aralkyl,heterocyclyl, heteroaryl or heteroarylalkyl, ortwo of R³, R^(3′), R⁴, R^(4′), R⁵, R^(5′), R⁶ or R^(6′) come together toform an aliphatic or aromatic ring; with the proviso that when X is Cl,all of R³, R^(3′), R⁴, R^(4′), R⁵, R^(5′), R⁶ and R^(6′) are nothydrogen; or when X is hydrogen, none of R³, R^(3′), R⁶ and R^(6′) aremethyl.

In particular embodiments, all but one of R³, R^(3′), R⁴, R^(4′), R⁵,R^(5′), R⁶ and R^(6′) is hydrogen.

In other particular embodiments, R³, R^(3′), R⁶ or R^(6′) are aryl orheteroaryl, optionally substituted with one or more groups selected fromhalogen, C₁-C₄ alkyl, alkyoxyl and haloalkyl.

In still other particular embodiments, R³, R^(3′), R⁶ or R^(6′) areheteroaryl, preferably pyridine.

In further embodiments, R³, R^(3′), R⁶ or R^(6′) are C₁-C₄ alkyl orcycloalkyl.

In more particular embodiments, the pyrrolidine with R³, R^(3′), R⁴,R^(4′), R⁵, R^(5′), R⁶ and R^(6′) substitution is selected from thefollowing moieties (arrow indicates point of attachment):

Specific hydroxyquinoline sulfonamide derivatives for use in the methodsdescribed herein are selected from the group consisting of:

-   5-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)quinolin-8-ol;-   5-(4-phenylpiperazin-1-yl)sulfonylquinolin-8-ol;-   5-(4-benzylpiperazin-1-yl)sulfonylquinolin-8-ol;-   5-isoindolin-2-ylsulfonylquinolin-8-ol;-   5-(2-phenylpyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-pyrrolidin-1-ylsulfonylquinolin-8-ol;-   5-(4-methylpiperazin-1-yl)sulfonylquinolin-8-ol;-   5-[(2-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;-   5-(3-(4-fluorophenyl)pyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-(6,8-dihydro-5H-1,7-naphthyridin-7-ylsulfonyl)quinolin-8-ol;-   5-[4-(5-chloro-2-pyridyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-[2-(o-tolyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-[2-(3-pyridyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-[(4-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;-   5-[2-(4-fluorophenyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-(2-benzylpyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-(2-cyclohexylpyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-[2-(4-methoxyphenyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-(2-isopropylpyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-[2-(4-pyridyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-[2-(2-pyridyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-[2-[2-(trifluoromethyl)phenyl]pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-(2-isobutylpyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-[(4-hydroxy-4-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;-   5-[(4-benzyl-1-piperidyl)sulfonyl]quinolin-8-ol;-   [1-[(8-hydroxy-5-quinolyl)sulfonyl]-4-piperidyl]-phenyl-methanone;-   1-[1-[(8-hydroxy-5-quinolyl)sulfonyl]-4-phenyl-4-piperidyl]ethanone;-   8-[(8-hydroxy-5-quinolyl)sulfonyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;-   methyl 4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazine-1-carboxylate;-   5-[4-(3-methoxypropyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   2-[4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazin-1-yl]benzonitrile;-   5-(3-azabicyclo[3.2.2]nonan-3-ylsulfonyl)quinolin-8-ol;-   5-[4-(2-phenylphenyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-(2,5-dimethylphenyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-(4-fluorophenyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-(2,3-dichlorophenyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[3-[4-(trifluoromethoxy)phenoxy]azetidin-1-yl]sulfonylquinolin-8-ol;-   5-[4-(2,3-dimethylphenyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-[(4-fluorophenyl)methyl]piperazin-1l-yl]sulfonylquinolin-8-ol;-   5-[(3-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;-   tert-butyl    4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazine-1-carboxylate;-   5-piperazin-1-ylsulfonylquinolin-8-ol;-   tert-butyl    4-[(8-hydroxy-5-quinolyl)sulfonyl]-3-methyl-piperazine-1-carboxylate;-   5-(2-methylpiperazin-1-yl)sulfonylquinolin-8-ol;-   7-methyl-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol;-   7-chloro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol;-   7-fluoro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol;-   5-[(2-methylpyrrolidin-1-yl)sulfonyl]quinolin-8-ol;-   5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-7-methyl-quinolin-8-ol;-   5-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]sulfonyl-7-methyl-quinolin-8-ol;-   7-chloro-5-[(2S)-2-methylpyrrolidin-1-yl]sulfonyl-quinolin-8-ol;-   7-chloro-5-[(2R)-2-methylpyrrolidin-1-yl]sulfonyl-quinolin-8-ol;-   7-bromo-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol;-   7-fluoro-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol;-   8-hydroxy-N-[(3-methoxyphenyl)methyl]-N-methyl-quinoline-5-sulfonamide;-   8-hydroxy-N-(4-methylbenzyl)quinoline-5-sulfonamide;-   N-benzyl-8-hydroxy-N-methylquinoline-5-sulfonamide;-   8-hydroxy-N-(4-methylphenyl)-N-methylquinoline-5-sulfonamide;-   8-hydroxy-N-methyl-N-phenethyl-quinoline-5-sulfonamide;-   N-[(4-fluorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;-   8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;-   8-hydroxy-N-methyl-N-[(1 S)-1-phenylethyl]quinoline-5-sulfonamide;-   N-[(2-fluorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;-   N-[(3-chlorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;-   8-hydroxy-N-methyl-N-(3-pyridylmethyl)quinoline-5-sulfonamide;-   8-hydroxy-N-methyl-N-(2-naphthylmethyl)quinoline-5-sulfonamide;-   N-benzyl-N-ethyl-8-hydroxy-quinoline-5-sulfonamide;-   N-benzyl-N-(2-dimethylaminoethyl)-8-hydroxy-quinoline-5-sulfonamide;-   5-(piperidin-1-yl)sulfonylquinolin-8-ol;-   5-(4-morpholin-1-yl)sulfonylquinolin-8-ol;-   N-[(4-(trifluoromethyl)phenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;-   N-ethyl-8-hydroxy-N-(4-pyridylmethyl)quinoline-5-sulfonamide;-   N,N-diethyl-8-hydroxy-quinoline-5-sulfonamide;-   8-hydroxy-N,7-dimethyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;-   7-chloro-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;-   7-bromo-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;    and-   7-fluoro-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide.

The compounds for use in the instant method may be selected from any oneor any combination of compounds identified herein, including compoundsdesignated 1-125 herein.

For use in the method, the compound or compounds of the presentinvention, described above, is typically provided as a pharmaceuticalcomposition wherein the compound or compounds is present in combinationwith a pharmaceutically acceptable carrier as described herein. Suchpharmaceutical compositions are also provided by this disclosure.

For use in the method, the compound(s) of the present invention,described above, may also be used in combination with another additionaltherapeutic agent.

The methods of the present invention may be used to treat or prevent aneurological or psychiatric disorder. In particular, exemplaryembodiments of the invention include methods of treating or preventingschizophrenia, major depression, a depressive phase of bipolar disorder,attention deficit disorder, attention deficit/hyperactivity disorder,substance dependency, or increased appetite associated with smokingcessation or antipsychotic use. Other significant indications includeage-associated cognitive symptoms, impulse control disorders, includingcompulsive gambling, sexual behavior, and other compulsive destructivebehaviors.

In addition to the psychiatric indications, the methods of the inventionmay also be used to treat neurological disorders. In one embodiment, themethod of the present invention comprises administering an effectiveamount of a compound described herein above in combination with L-DOPAfor treatment of Parkinson's disease. The compound can be administeredin combination with L-DOPA, concurrently or separately, with or withoutan aromatic L-amino acid decarboxylase inhibitor (AADC) such ascarbidopa, to prevent or inhibit COMT-mediated metabolism of L-DOPA.

III. Compounds

Also disclosed herein are the novel sulfonylquinolinol derivatives andnovel hydroxyquinoline sulfonamide derivatives described above which,preferably, are inhibitors of catechol O-methyltransferase (COMT)enzyme, and which are useful in the treatment or prevention ofneurological or psychiatric disorders or diseases in which COMT isinvolved. The compounds of the invention are characterized by theiractivity to inhibit the enzyme COMT. In preferred embodiments, thecompounds of the present invention are effective to inhibit the enzymeCOMT, in an assay which determines the inhibitory concentration (IC₅₀)for the conversion of the methyl donor S-adenosyl methionine toS-adenosyl homocysteine (SAH) as described herein, with a pIC₅₀ superioror equal to 4.5. In increasingly preferred embodiments, the pIC₅₀ as sodetermined is superior or equal to 6.0. In a more preferred embodiment,the pIC₅₀ as so determined is superior or equal to 7.0.

The ability of compounds within the scope of this invention to inhibitthe activity of catechol-O-methyltransferase (COMT) may be determined bymethods known to those in the art for measuring COMT inhibition. Onemethod for measuring COMT activity uses a homogenous time-resolvedfluorescent (HTRF) assay (Lina et al, 2012; kit from CisBio, Codolet,France). This assay measures the production of —S-adenosyl homocysteine(SAH) from the methyl donor S-adenosyl methionine. Using this assaypreferred compounds of the invention have a pIC₅₀ superior or equal to4.5. In increasingly preferred embodiments, the pIC₅₀ as so determinedis superior or equal to 6.0. In a more preferred embodiment, the pIC₅₀as so determined is superior or equal to 7.0.

Provided herein are COMT-inhibiting compounds in accordance with formulaI, or pharmaceutically acceptable salts thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;Z is selected from SO₂R¹ and SO₂NR²R³;R¹ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl and heteroarylalkyl, any of which may besubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino,oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl,CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄alkyl or (R⁴)₂ forms a carbocyclic ring;R² and R³ are independently selected from hydrogen and any of the groupsas defined for R¹, with the proviso that at least one of R² or R³ isdifferent from hydrogen; or R² and R³ may together form a 3-10 memberedmonocyclic, bicyclic or spirocyclic nitrogen-containing ring system thatcontains 0-3 (preferably 0-1) additional heteroatoms selected fromoxygen (O), nitrogen (N), and sulfur (S), and which may be furthersubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino,C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl,aralkyl, heterocyclyl, heteroaryl or heteroarylalkyl;with the proviso that when X is hydrogen and Z is SO₂R¹, R¹ is not C₁alkyl, C₄ alkyl, C₈ alkyl, phenyl, 4-methyphenyl, 4-methoxybenzyl,4-bromophenyl, 4-iodophenyl, 2,4,6-trimethylphenyl, CH(COMe)₂,CH(CO₂Et)₂, 4-BnOPh, tetrahydropyran or propylcyclopropane;or when X is H and Z is SO₂NR²R³, R² and R³ do not together form a1-piperidinyl ring substituted with an α-methyl group;or when X is Cl and Z is SO₂R¹, R¹ is not C₃ alkyl, C₄ alkyl or C₅-C₆cycloalkyl;or when X is Cl and Z is SO₂NR²R³, R² and R³ do not together form anunsubstituted, 1-pyrrolidinyl ring.

An additional embodiment of the above includes the proviso that when Xis F and Z is SO₂R¹, R¹ is not pyridyl, cyclopentyl and phenylsubstituted with fluoro, or trifluoromethyl.

A second additional embodiment of the above further includes the provisothat when X is Cl and Z is SO₂R¹, R¹ is not thiazolyl, pyridyl,pyridyl-N-oxide, and phenyl substituted with one or two groups selectedfrom fluoro, chloro, methyl, trifluoromethyl, phenyl and tert-butyl.

In particular embodiments, R¹ is selected from C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl,any of which may be substituted with one or more groups selected fromhalogen, C≡N, CF₃, OH, C₁-C₄ alkyl or alkenyl, C₁-C₄ alkoxy, aryloxy,nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₆ cycloalkyl, acyl, aryl,aralkyl, heterocyclyl or heteroaryl.

In other particular embodiments, Z is SO₂R¹ and R¹ is selected fromsubstituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstitutedC₃-C₁₀ cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl, substituted or unsubstituted C-attachedheterocyclyl, substituted or unsubstituted C-attached heteroaryl orsubstituted or unsubstituted heteroarylalkyl.

In still other particular embodiments, Z is SO₂R¹ and R¹ is selectedfrom C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, phenyl, naphthyl, aralkyl,C-attached piperidinyl, C-attached 1H-benzimidazolyl, C-attachedtetrahydro-2H-pyranyl and pyridinyl, any of which may be substitutedwith one or more groups selected from halogen, CF₃, C₁-C₄ alkyl, C₁-C₄alkoxy, C₃-C₆ cycloalkyl, substituted or unsubstituted phenyl,substituted or unsubstituted pyridinyl, substituted or unsubstitutedquinolinyl, substituted or unsubstituted 1H-indazolyl, substituted orunsubstituted aralkyl or acyl. Certain embodiments include the provisothat when X is fluorine and Z is SO₂R¹, R¹ is not cyclopentyl.

In further particular embodiments, when Z is SO₂NR²R³, each of R² and R³may be independently selected from hydrogen, C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl,any of which, excluding hydrogen, may be substituted with one or moregroups selected from halogen, C≡N, CF₃, C₁-C₄ alkyl or C₂-C₄ alkenyl,C₁-C₄ alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₆ cycloalkyl,aryl, aralkyl, heterocyclyl or heteroaryl; with the proviso that atleast one of R² and R³ is different from hydrogen.

In still further particular embodiments, each of R² and R³ may beindependently selected from hydrogen, C₁-C₄ alkyl, C₃-C₁₀ cycloalkyl,aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl, any ofwhich, excluding hydrogen, may be substituted with one or more groupsselected from halogen, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, amino, C₃-C₆cycloalkyl, aryl, heterocyclyl or heteroaryl.

In other particular embodiments, R² is selected from hydrogen orsubstituted or unsubstituted C₁-C₄ alkyl.

In still other particular embodiments, R³ is selected from C₁-C₄ alkyl,aryl, aralkyl, heteroaryl and heteroarylalkyl, any of which, excludinghydrogen, may be substituted with one or more groups selected fromhalogen, C₁-C₄ alkyl or C₁-C₄ alkoxy.

In further particular embodiments, when Z is SO₂NR²R³, R² and R³ maytogether form a 3-10 membered monocyclic, bicyclic or spirocyclicnitrogen-containing ring system that contains 0-3 additional heteroatomsselected from oxygen (O), nitrogen (N), and sulfur (S), and which may befurther substituted with one or more groups selected from halogen, C₁-C₄alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, arylalkoxy,nitro, amino, C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃,aryl, aralkyl, heterocyclyl, or heteroaryl.

In still further particular embodiments, the nitrogen-containing ringsystem formed by R² and R³ is a 4-7 membered monocyclic ring system or a8-10 membered bicyclic or spirocyclic nitrogen-containing ring system.In another selected embodiment the monocyclic, bicyclic or spirocyclicnitrogen-containing ring system contains 0-1 additional heteroatomsselected from oxygen (O), nitrogen (N), and sulfur (S).

In other particular embodiments, Z is SO₂NR²R³ with NR²R³ being asubstituted or unsubstituted pyrrolidinyl, substituted or unsubstitutedpiperidinyl, substituted or unsubstituted piperazinyl, substituted orunsubstituted azetidinyl, substituted or unsubstituted1,3,8-triazaspiro[4.5]decanyl, substituted or unsubstituteddihydroisoquinolinyl, substituted or unsubstituted dihydroisoindolyl,substituted or unsubstituted morpholinyl, substituted or unsubstituteddihydronaphthyridinyl or substituted or unsubstitutedazabicyclo[3.2.2]nonyl.

In still other particular embodiments, NR²R³ is a 1-pyrrolidinyl,1-piperidinyl, 1-piperazinyl, 1-azetidinyl,1,3,8-triazaspiro[4.5]dec-8-yl, 3,4-dihydro-2(1H)-isoquinolinyl,1,3-dihydro-2H-isoindol-2-yl, 4-morpholinyl,5,8-dihydronaphthyridin-7(6H)-yl, azabicyclo[3.2.2]non-3-yl which may befurther substituted with one or more groups selected from halogen, C≡N,CF₃, OH, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, arylalkoxy, amino,C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, aryl, aralkyl,heterocyclyl, or heteroaryl.

The group X in formula I, in selected embodiments, is selected fromhydrogen, halogen, trifluoromethyl, methyl and nitrile (C≡N); in furtherembodiments X in formula I is hydrogen, halogen, trifluoromethyl, ormethyl; in further embodiments of this group, said halogen is fluorineor chlorine. In one embodiment, X is fluorine. In another embodiment, Xis hydrogen. In another embodiment, X is trifluoromethyl.

Also provided herein are COMT-inhibiting compound in accordance withformula I, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from H, F, Br, I, C≡N, CF₃, and C₁-C₄ alkyl;Z is selected from SO₂R¹ and SO₂NR²R³;R¹ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl and heteroarylalkyl, any of which may besubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino,oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl,CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄alkyl or (R⁴)₂ forms a carbocyclic ring;R² and R³ are independently selected from hydrogen and any of the groupsas defined for R¹, with the proviso that at least one of R² or R³ isdifferent from hydrogen; or R² and R³ may together form a 3-10 memberedmonocyclic, bicyclic or spirocyclic nitrogen-containing ring system thatcontains 0-3 (preferably 0-1) additional heteroatoms selected fromoxygen (O), nitrogen (N), and sulfur (S), and which may be furthersubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino,C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl,aralkyl, heterocyclyl, heteroaryl or heteroarylalkyl;with the proviso that when X is hydrogen and Z is SO₂R¹, R¹ is not C₁alkyl, C₄ alkyl, C₈ alkyl, phenyl, 4-methyphenyl, 4-methoxybenzyl,4-bromophenyl, 4-iodophenyl, 2,4,6-trimethylphenyl, CH(COMe)₂,CH(CO₂Et)₂, 4-BnOPh, tetrahydropyran or propylcyclopropane; or when X isH and Z is SO₂NR²R³, R² and R³ do not together form a 1-piperidinyl ringsubstituted with an α-methyl group.

An additional embodiment of the above includes the proviso that when Xis F and Z is SO₂R¹, R¹ is not pyridyl, cyclopentyl and phenylsubstituted with fluoro, or trifluoromethyl.

A second additional embodiment of the above further includes the provisothat when X is Cl and Z is SO₂R¹, R¹ is not thiazolyl, pyridyl,pyridyl-N-oxide, and phenyl substituted with one or two groups selectedfrom fluoro, chloro, methyl, trifluoromethyl, phenyl and tert-butyl.

Also provided herein are COMT-inhibiting compound in accordance withformula I, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from halogen, C≡N, CF₃, and C₁-C₄ alkyl;Z is selected from SO₂R¹ and SO₂NR²R³;R¹ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl and heteroarylalkyl, any of which may besubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino,oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl,CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄alkyl or (R⁴)₂ forms a carbocyclic ring;R² and R³ are independently selected from hydrogen and any of the groupsas defined for R¹, with the proviso that at least one of R² or R³ isdifferent from hydrogen; or R² and R³ may together form a 3-10 memberedmonocyclic, bicyclic or spirocyclic nitrogen-containing ring system thatcontains 0-3 (preferably 0-1) additional heteroatoms selected fromoxygen (O), nitrogen (N), and sulfur (S), and which may be furthersubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino,C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl,aralkyl, heterocyclyl, heteroaryl or heteroarylalkyl;with the proviso that when X is Cl and Z is SO₂R¹, R¹ is not C₃ alkyl,C₄ alkyl or C₅-C₆ cycloalkyl;or when X is Cl and Z is SO₂NR²R³, R² and R³ do not together form anunsubstituted, 1-pyrrolidinyl ring.

An additional embodiment of the above includes the proviso that when Xis F and Z is SO₂R¹, R¹ is not pyridyl, cyclopentyl and phenylsubstituted with fluoro, or trifluoromethyl.

A second additional embodiment of the above further includes the provisothat when X is Cl and Z is SO₂R¹, R¹ is not thiazolyl, pyridyl,pyridyl-N-oxide, and phenyl substituted with one or two groups selectedfrom fluoro, chloro, methyl, trifluoromethyl, phenyl and tert-butyl.

In a specific embodiment, R¹ is ethyl, 2-propanyl, 2-methylpropyl,octyl, 3-cyclopropylpropyl, 4-methylbenzyl, 2-(4-methylphenyl)ethyl,cyclopentyl, cyclohexyl, 3-methylphenyl, 4-methylphenyl,2,4-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-tert-butylphenyl, 3-chlorophenyl,4-chlorophenyl, 4-fluorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl,4-fluoro-2-methylphenyl, 3-(quinolin-5-yl)phenyl, biphenyl-3-yl,3′-chloro-4′-fluorobiphenyl-3-yl, 3-(1H-indazol-4yl)phenyl,3-(pyridin-4-yl)phenyl, 2-naphthyl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 3-methylpyridin-4-yl, 1-(2,3-dimethylphenyl)pyridin-4-yl,4-piperidinyl, 1-(2,3-dichlorobenzoyl)piperidin-4-yl,(4-fluorobenzyl)piperidin-4-yl, 1-(4-fluorophenyl)-piperidin-4-yl,1-(2,3-dichlorobenzyl)piperidin-4-yl,1-(2-chlorobenzyl)-1H-benzimidazol-4-yl, tetrahydro-2H-pyran-4-yl.

The group X in formula I, in selected embodiments of thesulfonylquinolinol derivatives, is selected from hydrogen, halogen,trifluoromethyl, methyl and nitrile (C≡N); in further embodiments X informula I is hydrogen, halogen or methyl; in further embodiments of thisgroup, said halogen is fluorine or chlorine. In one embodiment, X isfluorine. In another embodiment, X is hydrogen. In another embodiment, Xis trifluoromethyl.

Also provided herein are COMT-inhibiting compound in accordance withformula II, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;Ar is aryl or heteroaryl, optionally substituted with one or more groupsselected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl,alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀ cycloalkyl, acyl,aryl, aralkyl, heterocyclyl, heteroaryl, CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂,where each R⁴ is independently C₁-C₄ alkyl or (R⁴)₂ forms a carbocyclicring;with the proviso that when X is hydrogen, R¹ is not phenyl,4-methyphenyl, 4-methoxybenzyl, 4-bromophenyl, 4-iodophenyl or2,4,6-trimethylphenyl.

In particular embodiments, Ar is heteroaryl, optionally substituted withone or more groups selected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl orC₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl, CON(R⁴)₂,SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄ alkyl or (R⁴)₂forms a carbocyclic ring.

In more particular embodiments, Ar is heteroaryl selected from thefollowing moieties (arrow indicates point of attachment):

In other particular embodiments, Ar is aryl, optionally substituted withone or more groups selected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl orC₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl, CON(R⁴)₂,SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄ alkyl or (R⁴)₂forms a carbocyclic ring.

In still other particular embodiments, Ar is phenyl, optionallysubstituted with one or more groups selected from halogen, C≡N, CF₃, OH,C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄ alkylamino,oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl,CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ is independently C₁-C₄alkyl or (R⁴)₂ forms a carbocyclic ring.

In more particular embodiments, Ar is phenyl optionally substituted withone or more groups selected from halogen, C₁-C₄ alkyl, alkoxyl orheteroaryl.

In further particular embodiments, Ar is selected from the followingmoieties (arrow indicates point of attachment):

Also provided herein are COMT-inhibiting compound in accordance withformula III, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from hydrogen, F, Br, I, C≡N, CF₃, and C₁-C₄ alkyl; andR¹ is selected from C₃-C₁₀ cycloalkyl, aryl, aralkyl, heteroaryl andheteroarylalkyl, any of which may be substituted with one or more groupsselected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl,alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀ cycloalkyl, acyl,aryl, aralkyl, heterocyclyl, heteroaryl, CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂,where each R⁴ is independently C₁-C₄ alkyl or (R⁴)₂ forms a carbocyclicring;with the proviso that when X is hydrogen, R¹ is not phenyl,4-methyphenyl, 4-methoxybenzyl, 4-bromophenyl, 4-iodophenyl,2,4,6-trimethylphenyl or 4-BnOPh.

The group X in formula III, in selected embodiments of thesulfonylquinolinol derivatives, is selected from hydrogen, halogen,methyl, trifluoromethyl, and nitrile (C≡N); in further embodiments X informula I is hydrogen, halogen or methyl; in further embodiments of thisgroup, said halogen is fluorine or chlorine. In one embodiment, X isfluorine. In another embodiment, X is hydrogen. In a further embodiment,X is trifluoromethyl.

In particular embodiments, R¹ is selected from the following moieties(arrow indicates point of attachment):

Also provided herein are COMT-inhibiting compound in accordance withformula IV, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl; andR³ is selected from hydrogen, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl,aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or acyl, any of whichmay be substituted with one or more groups selected from halogen, C≡N,CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro, amino, C₁-C₄alkylamino, oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl, heterocyclyl,heteroaryl, CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴ isindependently C₁-C₄ alkyl or (R⁴)₂ forms a carbocyclic ring.

In more particular embodiments, X is hydrogen and R³ is selected fromaralkyl, acyl, or aryl.

In further particular embodiments, R³ is selected from the followingmoieties (arrow indicates point of attachment):

Specific sulfonylquinolinol derivatives of the present invention arethose selected from the group consisting of:

-   5-tosylquinolin-8-ol;-   5-(4-fluorophenyl)sulfonylquinolin-8-ol;-   5-(3,4-dimethylphenyl)sulfonylquinolin-8-ol;-   5-(3,5-dimethylphenyl)sulfonylquinolin-8-ol;-   5-(4-tert-butylphenyl)sulfonylquinolin-8-ol;-   5-(3-phenylphenyl)sulfonylquinolin-8-ol;-   5-(m-tolylsulfonyl)quinolin-8-ol;-   5-(3,5-dichlorophenyl)sulfonylquinolin-8-ol;-   5-(4-chlorophenyl)sulfonylquinolin-8-ol;-   5-(2,4-dimethylphenyl)sulfonylquinolin-8-ol;-   5-[4-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;-   5-(2-naphthylsulfonyl)quinolin-8-ol;-   5-[3-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;-   5-(3-chlorophenyl)sulfonylquinolin-8-ol;-   5-(3,4-dichlorophenyl)sulfonylquinolin-8-ol;-   5-(2-pyridylsulfonyl)quinolin-8-ol;-   5-(4-pyridylsulfonyl)quinolin-8-ol;-   5-(4-methoxyphenyl)sulfonylquinolin-8-ol;-   5-(3-pyridylsulfonyl)quinolin-8-ol;-   5-(4-fluoro-2-methyl-phenyl)sulfonylquinolin-8-ol;-   5-[2-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;-   5-(benzenesulfonyl)quinolin-8-ol;-   5-[3-(4-pyridyl)phenyl]sulfonylquinolin-8-ol;-   5-[3-(3-chloro-4-fluoro-phenyl)phenyl]sulfonylquinolin-8-ol;-   5-[3-(5-quinolyl)phenyl]sulfonylquinolin-8-ol;-   5-[3-(1H-indazol-4-yl)phenyl]sulfonylquinolin-8-ol;-   5-[(3-methyl-4-pyridyl)sulfonyl]quinolin-8-ol;-   5-[1-[(2-chlorophenyl)methyl]benzimidazol-4-yl]sulfonylquinolin-8-ol;-   5-[2-(p-tolyl)ethylsulfonyl]quinolin-8-ol;-   5-cyclohexylsulfonylquinolin-8-ol;-   5-cyclopentylsulfonylquinolin-8-ol;-   5-(p-tolylmethylsulfonyl)quinolin-8-ol;-   5-ethylsulfonylquinolin-8-ol;-   5-(4-piperidylsulfonyl)quinolin-8-ol;-   5-[[1-[(4-fluorophenyl)methyl]-4-piperidyl]sulfonyl]quinolin-8-ol;-   5-[[1-[(2,3-dichlorophenyl)methyl]-4-piperidyl]sulfonyl]quinolin-8-ol;-   5-[[1-(4-fluorophenyl)-4-piperidyl]sulfonyl]quinolin-8-ol;-   5-[[1-(2,3-dimethylphenyl)-4-piperidyl]sulfonyl]quinolin-8-ol;-   7-iodo-5-(p-tolylsulfonyl)quinolin-8-ol;-   7-bromo-5-(p-tolylsulfonyl)quinolin-8-ol;-   7-chloro-5-(p-tolylsulfonyl)quinolin-8-ol;-   7-fluoro-5-(p-tolylsulfonyl)quinolin-8-ol;-   5-(p-tolylsulfonyl)-7-(trifluoromethyl)quinolin-8-ol; and-   5-cyclopentylsulfonyl-7-(trifluoromethyl)quinolin-8-ol.

Also provided herein are COMT-inhibiting compound in accordance withformula I, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;Z is SO₂NR²R³, wherein NR²R³ is a 1-pyrrolidinyl, 1-piperidinyl,1-piperazinyl, 1-azetidinyl, 1,3,8-triazaspiro[4.5]dec-8-yl,3,4-dihydro-2(1H)-isoquinolinyl, 1,3-dihydro-2H-isoindol-2-yl,4-morpholinyl, 5,8-dihydronaphthyridin-7(6H)-yl,azabicyclo[3.2.2]non-3-yl which may be further substituted with one ormore groups selected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄alkenyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, arylalkoxy, nitro, amino, C₁-C₄alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl, aralkyl,heterocyclyl, or heteroaryl;with the proviso that when X is H, NR²R³ do not together form a1-piperidinyl ring substituted with a α-methyl group;or when X is Cl, NR²R³ do not together form an unsubstituted,1-pyrrolidinyl ring.

In yet another particular embodiment, NR²R³ is selected from1-pyrrolidinyl, 2-methylpyrrolidin-1-yl, (2R)-2-methylpyrrolidin-1-yl,(2S)-2-methylpyrrolidin-1-yl, (3R,4R)-3,4-difluoropyrrolidin-1-yl,2-(propan-2-yl)pyrrolidin-1-yl, 2-(2-methylpropyl)pyrrolidin-1-yl,2-cyclohexylpyrrolidin-1-yl, 2-benzylpyrrolidin-1-yl,2-phenylpyrrolidin-1-yl, 2-(2-methylphenyl)pyrrolidin-1-yl,2-(4-fluorophenyl)pyrrolidin-1-yl, 3-(4-fluorophenyl)pyrrolidin-1-yl,2-(4-methoxyphenyl)pyrrolidin-1-yl,2-[2-(trifluoromethyl)phenyl]pyrrolidin-1-yl,2-(pyridin-2-yl)pyrrolidin-1-yl, 2-(pyridin-3-yl)pyrrolidin-1-yl,2-(pyridin-4-yl)pyrrolidin-1-yl, 1-piperidinyl, 2-phenylpiperidin-1-yl,3-phenylpiperidin-1-yl, 4-phenylpiperidin-1-yl,4-hydroxy-4-phenylpiperidin-1-yl, 4-acetyl-4-phenylpiperidin-1-yl,4-benzylpiperidin-1-yl, 4-benzoylpiperidin-1-yl, 1-piperazinyl,2-methylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-phenylpiperazin-1-yl,4-(2,3-dimethylphenyl)piperazin-1-yl,4-(2,5-dimethylphenyl)piperazin-1-yl, 4-(4-fluorophenyl)piperazin-1-yl,4-(2,3-dichlorophenyl)piperazin-1-yl,4-[4-(trifluoromethyl)phenyl]piperazin-1-yl,4-(2-cyanophenyl)piperazin-1-yl, 4-(biphenyl-2-yl)piperazin-1-yl,4-benzylpiperazin-1-yl, 4-(4-fluorobenzyl)piperazin-1-yl,4-(3-methoxypropyl)piperazin-1-yl, 4-(methoxycarbonyl)piperazin-1-yl,4-(tert-butoxycarbonyl)piperazin-1-yl,4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl,4-(5-chloropyridin-2-yl)piperazin-1-yl,4-[bis(4-fluorophenyl)methyl]piperazin-1-yl,4-(1,2-benzothiazol-3-yl)piperazin-1-yl,3,4-dihydroisoquinolin-2(1H)-yl, 1,3-dihydro-2H-isoindol-2-yl,5,8-dihydro-1,7-naphthyridin-7(6H)-yl,4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl,3-azabicyclo[3.2.2]non-3-yl or3-[4-(trifluoromethoxy)phenoxy]azetidin-1-yl.

Also provided herein are COMT-inhibiting compound in accordance withformula V, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;R² and R³ are independently selected from hydrogen, C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl,any of which may be substituted with one or more groups selected fromhalogen, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl, alkoxy, nitro,amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀ cycloalkyl, acyl, aryl, aralkyl,heterocyclyl, heteroaryl, CON(R⁴)₂, SO₂R⁴, or SO₂N(R⁴)₂, where each R⁴is independently C₁-C₄ alkyl or (R⁴)₂ forms a carbocyclic ring;with the proviso that at least one of R² or R³ is different fromhydrogen; or when X is H, R² and R³ do not together form a 1-piperidinylring substituted with a α-methyl group;or when X is Cl, R² and R³ do not together form an unsubstituted,1-pyrrolidinyl ring.

In particular embodiments, NR²R³ is selected from the following moieties(arrow indicates point of attachment):

Also provided herein are COMT-inhibiting compound in accordance withformula VI, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;R⁵, R^(5′), R⁶, R^(6′), R⁷ and R^(7′) are each independently selectedfrom hydrogen, halogen, hydroxyl, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino, C₁-C₄ alkoxycarbonyl,acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl, aralkyl, heterocyclyl,heteroaryl or heteroarylalkyl, ortwo of R⁵, R^(5′), R⁶, R^(6′), R⁷ and R^(7′) come together to form analiphatic or aromatic ring;with the proviso that when X is H, neither R⁶ nor R^(6′) are a methylgroup.

In particular embodiments, the piperidine with R⁵, R^(5′), R⁶, R^(6′),R⁷ and R^(7′) substitution is selected from the following moieties(arrow indicates point of attachment):

Also provided herein are COMT-inhibiting compound in accordance withformula VII, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;R³, R⁵, R^(5′), R⁶ and R^(6′) are each independently selected fromhydrogen, halogen, hydroxyl, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl,C₃-C₆ cycloalkyl, alkoxy, nitro, amino, C₁-C₄ alkoxycarbonyl, acyl,C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl, aralkyl, heterocyclyl, heteroarylor heteroarylalkyl, ortwo of R³, R⁵, R^(5′), R⁶ or R^(6′) come together to form an aliphaticor aromatic ring.

In particular embodiments, R⁵, R^(5′), R⁶ and R^(6′) are each hydrogen.

In other particular embodiments, the piperizine with R³, R⁵, R^(5′), R⁶and R^(6′) substitution is selected from the following moieties (arrowindicates point of attachment):

Also provided herein are COMT-inhibiting compound in accordance withformula VIII, or a pharmaceutically acceptable salt thereof:

wherein:X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄ alkyl;R³, R^(3′), R⁴, R^(4′), R⁵, R^(5′), R⁶ and R^(6′) are each independentlyselected from hydrogen, halogen, hydroxyl, C≡N, CF₃, OH, C₁-C₄ alkyl orC₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino, C₁-C₄alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl, aralkyl,heterocyclyl, heteroaryl or heteroarylalkyl, ortwo of R³, R^(3′), R⁴, R^(4′), R⁵, R^(5′), R⁶ or R^(6′) come together toform an aliphatic or aromatic ring;with the proviso that when X is Cl, all of R³, R^(3′), R⁴, R^(4′), R⁵,R^(5′), R⁶ and R^(6′) are not hydrogen.

In particular embodiments, all but one of R³, R^(3′), R⁴, R^(4′), R⁵,R^(5′), R⁶ and R^(6′) is hydrogen.

In other particular embodiments, R³, R^(3′), R⁶ or R^(6′) are aryl orheteroaryl, optionally substituted with one or more groups selected fromhalogen, C₁-C₄ alkyl, alkyoxyl and haloalkyl.

In still other particular embodiments, R³, R^(3′), R⁶ or R^(6′) areheteroaryl, preferably pyridine.

In further embodiments, R³, R^(3′), R⁶ or R^(6′) are C₁-C₄ alkyl orcycloalkyl.

In more particular embodiments, the pyrrolidone with R³, R^(3′), R⁴,R^(4′), R⁵, R^(5′), R⁶ and R^(6′) substitution is selected from thefollowing moieties (arrow indicates point of attachment):

Specific hydroxyquinoline sulfonamide derivatives for use in the methodsdescribed herein are selected from the group consisting of:

-   5-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)quinolin-8-ol;-   5-(4-phenylpiperazin-1-yl)sulfonylquinolin-8-ol;-   5-(4-benzylpiperazin-1-yl)sulfonylquinolin-8-ol;-   5-isoindolin-2-ylsulfonylquinolin-8-ol;-   5-(2-phenylpyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-pyrrolidin-1-ylsulfonylquinolin-8-ol;-   5-(4-methylpiperazin-1-yl)sulfonylquinolin-8-ol;-   5-[(2-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;-   5-(3-(4-fluorophenyl)pyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-(6,8-dihydro-5H-1,7-naphthyridin-7-ylsulfonyl)quinolin-8-ol;-   5-[4-(5-chloro-2-pyridyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-[2-(o-tolyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-[2-(3-pyridyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-[(4-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;-   5-[2-(4-fluorophenyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-(2-benzylpyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-(2-cyclohexylpyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-[2-(4-methoxyphenyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-(2-isopropylpyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-[2-(4-pyridyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-[2-(2-pyridyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-[2-[2-(trifluoromethyl)phenyl]pyrrolidin-1-yl]sulfonylquinolin-8-ol;-   5-(2-isobutylpyrrolidin-1-yl)sulfonylquinolin-8-ol;-   5-[(4-hydroxy-4-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;-   5-[(4-benzyl-1-piperidyl)sulfonyl]quinolin-8-ol;-   [1-[(8-hydroxy-5-quinolyl)sulfonyl]-4-piperidyl]-phenyl-methanone;-   1-[1-[(8-hydroxy-5-quinolyl)sulfonyl]-4-phenyl-4-piperidyl]ethanone;-   8-[(8-hydroxy-5-quinolyl)sulfonyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;-   methyl 4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazine-1-carboxylate;-   5-[4-(3-methoxypropyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   2-[4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazin-1-yl]benzonitrile;-   5-(3-azabicyclo[3.2.2]nonan-3-ylsulfonyl)quinolin-8-ol;-   5-[4-(2-phenylphenyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-(2,5-dimethylphenyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-(4-fluorophenyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-(2,3-dichlorophenyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[3-[4-(trifluoromethoxy)phenoxy]azetidin-1-yl]sulfonylquinolin-8-ol;-   5-[4-(2,3-dimethylphenyl)piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonylquinolin-8-ol;-   5-[(3-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;-   tert-butyl    4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazine-1-carboxylate;-   5-piperazin-1-ylsulfonylquinolin-8-ol;-   tert-butyl    4-[(8-hydroxy-5-quinolyl)sulfonyl]-3-methyl-piperazine-1-carboxylate;-   5-(2-methylpiperazin-1-yl)sulfonylquinolin-8-ol;-   7-methyl-5-pyrrolidin-1-yl sulfonyl-quinolin-8-ol;-   7-chloro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol;-   7-fluoro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol;-   5-[(2-methylpyrrolidin-1-yl)sulfonyl]quinolin-8-ol;    5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-7-methyl-quinolin-8-ol;-   5-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]sulfonyl-7-methyl-quinolin-8-ol;-   7-chloro-5-[(2S)-2-methylpyrrolidin-1-yl]sulfonyl-quinolin-8-ol;-   7-chloro-5-[(2R)-2-methylpyrrolidin-1-yl]sulfonyl-quinolin-8-ol;-   7-bromo-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol;-   7-fluoro-5-pyrrolidin-1-yl sulfonyl-quinolin-8-ol;-   8-hydroxy-N-[(3-methoxyphenyl)methyl]-N-methyl-quinoline-5-sulfonamide;-   8-hydroxy-N-(4-methylbenzyl)quinoline-5-sulfonamide;-   N-benzyl-8-hydroxy-N-methylquinoline-5-sulfonamide;-   8-hydroxy-N-(4-methylphenyl)-N-methylquinoline-5-sulfonamide;-   8-hydroxy-N-methyl-N-phenethyl-quinoline-5-sulfonamide;-   N-[(4-fluorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;-   8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;-   8-hydroxy-N-methyl-N-[(1 S)-1-phenylethyl]quinoline-5-sulfonamide;-   N-[(2-fluorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;-   N-[(3-chlorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;-   8-hydroxy-N-methyl-N-(3-pyridylmethyl)quinoline-5-sulfonamide;-   8-hydroxy-N-methyl-N-(2-naphthylmethyl)quinoline-5-sulfonamide;-   N-benzyl-N-ethyl-8-hydroxy-quinoline-5-sulfonamide;-   N-benzyl-N-(2-dimethylaminoethyl)-8-hydroxy-quinoline-5-sulfonamide;-   5-(piperidin-1-yl)sulfonylquinolin-8-ol;-   5-(4-morpholin-1-yl)sulfonylquinolin-8-ol;-   N-[(4-(trifluoromethyl)phenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;-   N-ethyl-8-hydroxy-N-(4-pyridylmethyl)quinoline-5-sulfonamide;-   N,N-diethyl-8-hydroxy-quinoline-5-sulfonamide;-   8-hydroxy-N,7-dimethyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;-   7-chloro-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;-   7-bromo-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;    and-   7-fluoro-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide.

In some embodiments, the present invention provides prodrugs of thecompounds described herein. The term “prodrug” refers to an agent thatis converted into a biologically active form in vivo. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the parent compound. They may, for instance, be bioavailable byoral administration whereas the parent compound is not. The prodrug mayalso have improved solubility in pharmaceutical compositions over theparent drug. A prodrug may be converted into the parent drug by variousmechanisms, including enzymatic processes and metabolic hydrolysis.Typical examples of prodrugs include compounds that have biologicallylabile protecting groups on a functional moiety of the active compound.Prodrugs include compounds that can be oxidized, reduced, aminated,deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed,alkylated, dealkylated, acylated decacylated, phosphorylated ordephosphorylated to produce the active compounds.

Prodrugs may be prepared by any variety of synthetic methods orappropriate adaptations presented in the chemical literature or as insynthetic or organic chemistry text books, such as those provide inGreen's Protective Groups in Organic Synthesis, Wiley, 4^(th) Edition(2007) Peter G. M. Wuts and Theodora W. Green; March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition(2007) Michael B. Smith and Domino Reactions in Organic Synthesis, Wiley(2006) Lutz F. Tietze, hereby incorporated by reference. Furtherinformation on the use of prodrugs may be found in Pro-drugs as NovelDelivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987(Ed. E. B. Roche, American Pharmaceutical Association), also herebyincorporated by reference.

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compoundsdisclosed herein with certain moieties known to those skilled in the artas ‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Some non-limiting examples of prodrugs in accordance with the inventioninclude: (i) where the exemplary compound contains a carboxylic acidfunctionality which is functionalized into a suitably metabolicallylabile group (esters, carbamates, etc.); (ii) where the exemplarycompound contains an alcohol functionality which is functionalized intoa suitably metabolically labile group (ethers, esters, carbamates,acetals, ketals, etc.); and (iii) where the exemplary compound containsa primary or secondary amino functionality, or an amide which arefunctionalized into a suitably metabolically labile group, e.g., ahydrolysable group (amides, carbamates, ureas, phosphonates, sulfonates,etc.). Further examples of replacement groups in accordance with theforegoing examples and examples of other prodrug types may be found inthe aforementioned references.

IV. Indications

As discussed above, the COMT-inhibiting compounds of the presentinvention can be used for treating neuropsychiatric and neurologicaldiseases for which inhibiting COMT provides a theraputic benefit.

Significant psychiatric indications, as discussed above, include, butare not limited to ADHD, obsessive-compulsive disorder, alcoholism andother addictions, depression, biopolar disorder, age-associatedcognitive symptoms, impulse control disorders, including compulsivegambling, sexual behavior, and other compulsive destructive behaviors,in particular, schizophrenia. Among the preferred neurological diseasesis treating Parkinson's disease, preferably when co-administered withL-DOPA, with or without a aromatic L-amino acid decarboxylase inhibitor(AADC) such as carbidopa, by preventing COMT-mediated metabolism ofL-DOPA.

In one embodiment, a method for treating conditions in which inhibitionof COMT enzyme is beneficial comprises administering to a patient inneed thereof a COMT-inhibiting compound described hereinabove for use inthe present methods. Such conditions include, but are not limited to,those provided in WO 2011/109254, the contents of which are incorporatedherein by reference.

In a specific embodiment, a method for treating schizophrenia orpsychosis comprises administering to a patient in need thereof aCOMT-inhibiting compound described hereinabove for use in the presentmethods. The Diagnostic and Statistical Manual of Mental Disorders(DSM-IV-TR) (2000, American Psychiatric Association, Washington, D.C.)provides a diagnostic tool that includes paranoid, disorganized,catatonic or undifferentiated schizophrenia and substance-inducedpsychotic disorders. As used herein, the term “schizophrenia orpsychosis” includes the diagnosis and classification of these mentaldisorders as described in DSM-IV-TR and the term is intended to includesimilar disorders described in other sources. Disorders and conditionsencompassed herein include, but are not limited to, conditions ordiseases such as schizophrenia or psychosis, including schizophrenia(paranoid, disorganized, catatonic, undifferentiated, or residual type),schizophreniform disorder, schizoaffective disorder, for example of thedelusional type or the depressive type, delusional disorder, psychoticdisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (for example psychosis induced by alcohol, amphetamine,cannabis, cocaine, hallucinogens, inhalants, opioids, phencyclidine,ketamine and other dissociative anaesthetics, and otherpsychostimulants), psychosispsychotic disorder, psychosis associatedwith affective disorders, brief reactive psychosis, schizoaffectivepsychosis, “schizophrenia-spectrum” disorders such as schizoid orschizotypal personality disorders, personality disorder of the paranoidtype, personality disorder of the schizoid type, illness associated withpsychosis (such as major depression, manic depressive (bipolar)disorder, Alzheimer's disease and post-traumatic stress syndrome),including both the positive and the negative symptoms of schizophreniaand other psychoses.

In another specific embodiment, a method for treating cognitivedisorders comprises administering to a patient in need thereof aCOMT-inhibiting compound described hereinabove for use in the presentmethods. The DSM-IV-TR also provides a diagnostic tool that includescognitive disorders including dementia, delirium, amnestic disorders andage-related cognitive decline. As used herein, the term “cognitivedisorders” includes the diagnosis and classification of these disordersas described in DSM-IV-TR and the term is intended to include similardisorders described in other sources. Disorders and conditionsencompassed herein include, but are not limited to, disorders thatcomprise as a symptom a deficiency in attention and/or cognition, suchas dementia (associated with Alzheimer's disease, ischemia,multi-infarct dementia, trauma, intracranial tumors, cerebral trauma,vascular problems or stroke, alcoholic dementia or other drug-relateddementia, AIDS, HIV disease, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt Jacob disease, perinatal hypoxia, othergeneral medical conditions or substance abuse), mild cognativeimpairment, multi-infarct dementia, Lewy body dementia, AIDS-relateddementia, and Fronto temperal dementia, delirium, amnestic disorders orage related cognitive decline.

In another specific embodiment, a method for treating anxiety disorderscomprises administering to a patient in need thereof a COMT-inhibitingcompound described hereinabove for use in the present methods. TheDSM-IV-TR also provides a diagnostic tool that includes anxietydisorders as generalized anxiety disorder, obsessive-compulsive disorderand panic attack. As used herein, the term “anxiety disorders” includesthe diagnosis and classification of these mental disorders as describedin DSM-IV-TR and the term is intended to include similar disordersdescribed in other sources. Disorders and conditions encompassed hereininclude, but are not limited to, anxiety disorders such as, acute stressdisorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder and anxietydue to a general medical condition.

In another specific embodiment, a method for treating substance-relateddisorders and addictive behaviors comprises administering to a patientin need thereof a COMT-inhibiting compound described hereinabove for usein the present methods. The DSM-IV-TR also provides a diagnostic toolthat includes persisting dementia, persisting amnestic disorder,psychotic disorder or anxiety disorder induced by substance abuse, andtolerance of, dependence on or withdrawal from substances of abuse. Asused herein, the term “substance-related disorders and addictivebehaviors” includes the diagnosis and classification of these mentaldisorders as described in DSM-IV-TR and the term is intended to includesimilar disorders described in other sources. Disorders and conditionsencompassed herein include, but are not limited to, substance-relateddisorders and addictive behaviors, such as substance-induced delirium,persisting dementia, persisting amnestic disorder, psychotic disorder oranxiety disorder, drug addiction, tolerance, and dependence orwithdrawal from substances including alcohol, amphetamines, cannabis,cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine,sedatives, hypnotics or anxiolytics.

In another specific embodiment, a method for treating obesity or eatingdisorders associated with excessive food intake, and complicationsassociated therewith, comprises administering to a patient in needthereof a COMT-inhibiting compound described hereinabove for use in thepresent methods. At present, obesity is included in the tenth edition ofthe International Classification of Diseases and Related Health Problems(ICD-10) (1992 World Health Organization) as a general medicalcondition. The DSM-IV-TR also provides a diagnostic tool that includesobesity in the presence of psychological factors affecting medicalcondition. As used herein, the term “obesity or eating disordersassociated with excessive food intake” includes the diagnosis andclassification of these medical conditions and disorders described inICD-10 and DSM-IV-TR and the term is intended to include similardisorders described in other sources. Disorders and conditionsencompassed herein include, but are not limited to, obesity, bulimianervosa and compulsive eating disorders.

In another specific embodiment, a method for treating mood anddepressive disorders comprises administering to a patient in needthereof a COMT-inhibiting compound described hereinabove for use in thepresent methods. As used herein, the term “mood and depressivedisorders” includes the diagnosis and classification of these medicalconditions and disorders described in the DSM-IV-TR and the term isintended to include similar disorders described in other sources.Disorders and conditions encompassed herein include, but are not limitedto, bipolar disorders, mood disorders including depressive disorders,major depressive episode of the mild, moderate or severe type, a manicor mixed mood episode, a hypomanic mood episode, a depressive episodewith atypical features, a depressive episode with melancholic features,a depressive episode with catatonic features, a mood episode withpostpartum onset, post-stroke depression; major depressive disorder,dysthymic disorder, minor depressive disorder, premenstrual dysphoricdisorder, post-psychotic depressive disorder of schizophrenia, a majordepressive disorder superimposed on a psychotic disorder such asdelusional disorder or schizophrenia, a bipolar disorder, for example,bipolar I disorder, bipolar II disorder, cyclothymic disorder,depression including unipolar depression, seasonal depression andpost-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), mood disorders due to a general medicalcondition, and substance-induced mood disorders.

In another specific embodiment, a method for treating pain comprisesadministering to a patient in need thereof a COMT-inhibiting compounddescribed hereinabove for use in the present methods. Particular painembodiments are bone and joint pain (osteoarthritis), repetitive motionpain, dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain and neuropathic pain.

In other specific embodiments, the COMT-inhibiting compounds describedhereinabove for use in the present methods can be used to treat othertypes of cognitive, learning and mental related disorders including, butnot limited to, learning disorders, such as a reading disorder, amathematics disorder, or a disorder of written expression,attention-deficit/hyperactivity disorder, age-related cognitive decline,pervasive developmental disorder including autistic disorder, attentiondisorders such as attention-deficit hyperactivity disorder (ADHD) andconduct disorder; an NMDA receptor-related disorder, such as autism,depression, benign forgetfulness, childhood learning disorders andclosed head injury; a neurodegenerative disorder or condition, such asneurodegeneration associated with traumatic brain injury, stroke,cerebral infarct, epileptic seizure, neurotoxin poisoning, orhypoglycemia-induced neurodegeneration; multi-system atrophy; movementdisorders, such as akinesias and akinetic-rigid syndromes (including,Parkinson's disease, drug-induced parkinsonism, post-encephaliticparkinsonism, progressive supranuclear palsy, multiple system atrophy,corticobasal degeneration, parkinsonism-ALS dementia complex and basalganglia calcification), medication-induced parkinsonism (such as,neuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Huntington's disease, dyskinesia associated with dopamineagonist therapy, Gilles de la Tourette's syndrome, epilepsy, muscularspasms and disorders associated with muscular spasticity or weaknessincluding tremors; dyskinesias, including tremor (such as, rest tremor,postural tremor, intention tremor and essential tremor), restless legsyndrome, chorea (such as Sydenham's chorea, Huntington's disease,benign hereditary chorea, neuroacanthocytosis, symptomatic chorea,drug-indufced chorea and hemiballism), myoclonus (including, generalisedmyoclonus and focal myoclonus), tics (including, simple tics, complextics and symptomatic tics), dystonia (including, generalised,iodiopathic, drug-induced, symptomatic, paroxymal, and focal (such asblepharospasm, oromandibular, spasmodic, spasmodic torticollis, axialdystonia, hemiplegic and dystonic writer's cramp)); urinaryincontinence; neuronal damage (including ocular damage, retinopathy ormacular degeneration of the eye, tinnitus, hearing impairment and loss,and brain edema); emesis; and sleep disorders, including insomnia andnarcolepsy.

Of the disorders above, the treatment of schizophrenia, bipolardisorder, depression, including unipolar depression, seasonal depressionand post-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), learning disorders, pervasive developmentaldisorders, including autistic disorder, attention disorders includingAttention-Deficit Hyperactivity Disorder, autism, tic disordersincluding Tourette's disorder, anxiety disorders including phobia andpost traumatic stress disorder, cognitive disorders associated withdementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease,spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment andloss are of particular importance.

In particularly desirable embodiments, the COMT-inhibiting compounds,including the compounds of the present invention, are useful fortreating Alzheimer's disease. Accordingly, a method for treatingAlzheimer's disease comprises administering to a patient in need thereofa COMT-inhibiting compound described hereinabove for the presentmethods.

In other particularly desirable embodiments, the COMT-inhibitingcompounds, including the compounds of the present invention, are usefulfor treating Parkinson's disease. Accordingly, a method for treatingParkinson's disease comprises administering to a patient in need thereofa COMT-inhibiting compound described hereinabove for the presentmethods.

In yet other particularly desirable embodiments, the COMT-inhibitingcompounds, including the compounds of the present invention, are usefulfor treating mild cognitive impairment. Accordingly, a method fortreating mild cognitive impairment comprises administering to a patientin need thereof a COMT-inhibiting compound described hereinabove for thepresent methods.

In still other particularly desirable embodiments, the COMT-inhibitingcompounds, including the compounds of the present invention, are usefulfor treating cognitive, learning and mental related disorders inpatients with neurodegeneration associated with traumatic brain injury.Accordingly, a method for treating cognitive, learning and mentalrelated disorders in patients with neurodegeneration associated withtraumatic brain injury comprises administering a COMT-inhibitingcompound described hereinabove for the present methods.

In further particularly desirable embodiments, the COMT-inhibitingcompounds, including the compounds of the present invention, are usefulfor treating schizophrenia. Accordingly, a method for treating treatingschizophrenia comprises administering to a patient in need thereof aCOMT-inhibiting compound described hereinabove for the present methods.

The subject COMT-inhibiting compounds, including the compounds of thepresent invention, are useful in methods for the prevention, treatment,control, amelioration, or reduction of risk of the diseases, disordersand conditions noted herein.

V. Combination Therapies

The subject COMT-inhibiting compounds, including the compounds of thepresent invention, are further useful in a method for the prevention ortreatment of the aforementioned diseases, disorders and conditions incombination with other agents. In many instances, the combination of thedrugs together is safer or more effective than either drug alone; thecompounds of the present invention and the other active ingredients mayoften be used in lower doses than when each is used singly. The drug(s)in the combination may be administered contemporaneously or sequentially(i.e. one preceding or following the other, at any appropriate timeinterval). When administered contemporaneously, the drugs may beadministered separately, or a single dosage form may contain both activeagents.

Accordingly, the subject compounds may be used in combination with otheragents which are known to be beneficial in the subject indications, orother drugs that affect receptors or enzymes that either increase theefficacy, safety, convenience, or reduce unwanted side effects ortoxicity of the compounds of the present invention. It will beappreciated that any of the drugs listed herein may be in the form of apharmaceutically acceptable salt.

In a particularly preferred embodiment, the subject compound is employedin combination with levodopa, with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide. In otherembodiments, the COMT inhibitor of the invention is administered incombination with anticholinergics such as biperiden and trihexyphenidyl(benzhexol) hydrochloride, other COMT inhibitors such as entacapone,MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists,cholinergic agonists, NMDA receptor antagonists, serotonin receptorantagonists and dopamine receptor agonists such as alentemol,bromocriptine, fenoldopam, lisuride, naxagolide, pergolide andpramipexole.

In another embodiment, the subject compound may be employed incombination with a neuroleptic or antipsychotic agent, orpharmaceutically acceptable salts thereof. Classes of neuroleptic agentsinclude phenothiazines; thioxanthenes; heterocyclic dibenzazepines;butyrophenones; diphenylbutylpiperidines; indolones, such asacepromazine, amisulpride, amoxapine, aripiprazole, asenapine,benperidol, bifeprunox, blonanserin, brexpiprazole, bromperidol,bupropion, busprione, capuride, cariprazine, carpipramine,chlorpromazine, chlorprothixene, clocapramine, clopenthixol,cloperidone, clotiapine, clozapine, cyamemazine, dexclamol, divalproex,dixyrazine, droperidol, flupentixol tiotixene, flupentixol,fluphenazine, fluphenazine, fluspirilene, haloperidol, hydroxyzine,iloperidone, levomepromazine, loxapine, lurasidone, melperone,mesoridazine, molindone, moperone, mosapramine, nefazodone, nemonapride,olanzapine, paliperidone, penfluridol, perazine, pericyazine, perlapine,perospirone, perphenazine, perphenazine, phenelzine, pimavanserin,pimozide, pipamperone, pipotiazine, prochlorperazine, promazine,promethazine, prothipendyl, quetiapine, remoxipride, risperidone,roletamide, sertindole, sulpiride, sultopride, thioproperazine,thioridazine, thiothixene, timiperone, tranylcypromaine, trazodone,trepipam, trifluoperazine, triflupromazine, trimipramine, veralipride,zicronapine, ziprasidone, zotepine, or zuclopenthixol.

In one embodiment, the subject compound may be employed in combinationwith anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen,vitamin E, and anti-amyloid antibodies.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antianxiety agents,cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minortranquilizers, melatonin agonists and antagonists, melatonergic agents,benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as:adinazolam, allobarbital, alonimid, alprazolam, amitriptyline,amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam,butabarbital, butalbital, capuride, carbocloral, chloral betaine,chloral hydrate, clonazepam, clorazepate, chlordiazepoxide, clorethate,cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone,divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol,etomidate, fenobam, flupentixol, fiurazepam, fluvoxamine, fluoxetine,fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium,lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin,mephobarbital, meprobamate, methaqualone, midaflur, midazolam,nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde,paroxetine, pentobarbital, perlapine, phenelzine, phenobarbital,prazepam, propofol, protriptyline, quazepam, reclazepam, roletamide,secobarbital, sertraline, suproclone, temazepam, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon,zolazepam, or zolpidem.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT1A agonists orantagonists, especially 5-HT1A partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid,phenelzine, tranylcypromine and selegiline; moclobemide; venlafaxine;duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone andviloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate,diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof.

VI. Formulation and Administration

The invention provides a method for administering a COMT inhibitingcompound as provided herein to a patient suffering from a condition, orprone to a condition, that is responsive to treatment or prevention withthe compound. The method comprises administering, e.g. orally orparenterally, a therapeutically effective amount of the compound,preferably provided as part of a pharmaceutical preparation.

The invention also provides pharmaceutical preparations comprising aCOMT-inhibiting compound as provided herein in combination with apharmaceutical excipient.

Modes of administration include administration by injection, e.g.parenteral, intravenous, intraarterial, intramuscular, subcutaneous, andintrathecal, as well as pulmonary, rectal, transdermal, transmucosal,and oral delivery.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, or other bovine, ovine, equine, canine,feline, or rodent, such as mouse, species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration.

Suitable formulation types for parenteral administration includeready-for-injection solutions, dry powders for combination with asolvent prior to use, suspensions ready for injection, dry insolublecompositions for combination with a vehicle prior to use, emulsions andliquid concentrates for dilution prior to administration.

The pharmaceutical carrier(s) employed may be solid or liquid. Liquidcarriers can be used in the preparation of solutions, emulsions,suspensions and pressurized compositions. The compounds are dissolved orsuspended in a pharmaceutically acceptable liquid excipient. Suitableexamples of liquid carriers for parenteral administration include, butare not limited to, water (which may contain additives, e.g., cellulosederivatives, preferably sodium carboxymethyl cellulose solution),phosphate buffered saline solution (PBS), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) and their derivatives,and oils (e.g., fractionated coconut oil and arachis oil). The liquidcarrier can contain other suitable pharmaceutical additives including,but not limited to, the following: solubilizers, suspending agents,emulsifiers, buffers, thickening agents, colors, viscosity regulators,preservatives, stabilizers and osmolarity regulators.

Exemplary excipients include, without limitation, carbohydrates,inorganic salts, antimicrobial agents, antioxidants, surfactants,buffers, acids, bases, and combinations thereof. A carbohydrate such asa sugar, a derivatized sugar such as an alditol, aldonic acid, anesterified sugar, and/or a sugar polymer may be present as an excipient.Specific carbohydrate excipients include, for example: monosaccharides,such as fructose, maltose, galactose, glucose, D-mannose, sorbose, andthe like; disaccharides, such as lactose, sucrose, trehalose,cellobiose, and the like; polysaccharides, such as raffinose,melezitose, maltodextrins, dextrans, starches, and the like; andalditols, such as mannitol, xylitol, maltitol, lactitol, xylitol,sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.

The excipient can also include an inorganic salt or buffer including,but not limited to, citric acid, sodium chloride, potassium chloride,sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodiumphosphate dibasic, and combinations thereof.

A surfactant may be present as an excipient. Exemplary surfactantsinclude, but are not limited to, polysorbates such as Tween 20 and Tween80 and pluronics such as F68 and F88 (both available from BASF, MountOlive, N.J.); sorbitan esters; lipids, such as phospholipids such aslecithin and other phosphatidyl cholines, phosphatidyl ethanolamines(although preferably not in liposomal form), and fatty acids and fattyesters.

Acids or bases may be present as an excipient in the preparation.Nonlimiting examples of acids that can be used include those acidsselected from the group consisting of hydrochloric acid, acetic acid,phosphoric acid, citric acid, malic acid, lactic acid, formic acid,trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid,sulfuric acid, fumaric acid, and combinations thereof. Examples ofsuitable bases include, without limitation, bases selected from thegroup consisting of sodium hydroxide, sodium acetate, ammoniumhydroxide, potassium hydroxide, ammonium acetate, potassium acetate,sodium phosphate, potassium phosphate, sodium citrate, sodium formate,sodium sulfate, potassium sulfate, potassium fumarate, and combinationsthereof.

For parenteral administration, the carrier can also be an oily estersuch as ethyl oleate and isopropyl myristate. Sterile carriers areuseful in sterile liquid form compositions for parenteraladministration. Sterile liquid pharmaceutical compositions, solutions orsuspensions can be utilized by, for example, intraperitoneal injection,subcutaneous injection, intravenously, or topically. The compositionscan also be administered intravascularly or via a vascular stent.

For pressurized compositions, the liquid carrier can be a halogenatedhydrocarbon or other pharmaceutically acceptable propellant. Suchpressurized compositions may also be lipid encapsulated for delivery viainhalation. For administration by intranasal or intrabronchialinhalation or insufflation, the compositions may be formulated into anaqueous or partially aqueous solution, which can then be utilized in theform of an aerosol.

The compositions may be administered topically, as a solution, cream, orlotion, by formulation with pharmaceutically acceptable vehiclescontaining the active compound. The compositions can be in a formsuitable for use in transdermal devices.

The compositions of this invention may be orally administered, informulations such as capsules, tablets, powders or granules, or assuspensions or solutions in water or non-aqueous media. In the case oftablets for oral use, carriers that are commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried corn starch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

The amount of the compound in the composition will vary depending on anumber of factors, but will optimally be a therapeutically effectivedose when the composition is stored in a unit dose container (e.g., avial). In addition, the pharmaceutical preparation can be housed in asyringe. A therapeutically effective dose can be determinedexperimentally by repeated administration of increasing amounts of theCOMT-inhibiting compound in order to determine which amount produces aclinically desired endpoint.

The amount of any individual excipient in the composition will varydepending on the activity of the excipient and particular needs of thecomposition. Typically, the optimal amount of any individual excipientis determined through routine experimentation, i.e., by preparingcompositions containing varying amounts of the excipient (ranging fromlow to high), examining the stability and other parameters, and thenfurther exploring the range at which optimal performance is attainedwith no significant adverse effects. Generally, however, the excipientwill be present in the composition in an amount of about 1% to about 99%by weight, preferably from about 5%-98% by weight, more preferably fromabout 15-95% by weight of the excipient, with concentrations less than30% by weight most preferred.

The foregoing pharmaceutical excipients, along with other excipients,are described in “Remington: The Science & Practice of Pharmacy”, 21sted., Williams & Williams, (2005), the “Physician's Desk Reference”, 67thed., PDR Network, Montvale, N.J. (2013), and Kibbe, A. H., “Handbook ofPharmaceutical Excipients”, 7th Edition, Pharmaceutical Press,Washington, D.C., 2012.

The dose of the compounds according to the invention to be administered,both unit dosage and dosing schedule, will vary depend upon the age,weight, and general condition of the subject, as well as the desiredtherapeutic effect, the route of administration, and the duration of thetreatment. The compounds of the invention are administered to thepatient in therapeutically effective amounts. Methods are known to thoseskilled in the art to adjust the dose to obtain maximal benefit.Generally, dosage levels of between 0.001 to 10 mg/kg of body weightdaily are administered to the patient. The dosage range will generallybe about 0.5 mg to 1.0 g per patient per day, which may be administeredin single or multiple doses. In one embodiment, the dosage range will beabout 0.5 mg to 500 mg per patient per day; in another embodiment about0.5 mg to 200 mg per patient per day; and in yet another embodimentabout 5 mg to 50 mg per patient per day. The compounds may beadministered on a regimen of 1 to 4 times per day, such as once or twiceper day.

These and other aspects of the invention will be realized upon closerinspection of the specification as a whole.

EXAMPLES

The present compounds can be prepared and evaluated according toprocedures provided in the following Examples. The following Examplesfurther describe, but do not limit, the scope of the invention.

COMT Inhibition Assay Procedure

The ability of compounds to inhibit the activity ofcatechol-O-methyltransferase (COMT) was determined by a homogenoustime-resolved fluorescent (HTRF) assay (Lina et al, 2012; kit fromCisBio, Codolet, France). This assay measures the production ofS-adenosyl homocysteine (SAH) from the methyl donor S-adenosylmethionine. Recombinant human membrane bound COMT (MB-COMT; M51Avariant) was expressed in HEK 293F cells using 293Fectin (LifeTechnologies, Gent, Belgium) and membranes prepared. The membranes werere-suspended in buffer (20 mM Tris/HCl pH 7; 10 mM glycerol; 2 mM MgCl₂;10 mM NaCl), aliquoted and stored at −80° C. Recombinant human solubleCOMT(S-COMT), Val158 variant and a hexa-His tag on the N-terminus, waspurified using Ni-NTA chromatography, the His tag removed and stored inbuffer as above.

For the human MB-COMT assay, membranes (62 ng/well) were incubated withSAM (20 μM final, CisBio) and dopamine (1.5 μM final; Sigma H8502,Diegem, Belgium) in the presence or absence of varying concentrations(typically 10 concentrations ranging from 10 μM to 0.1 nM) of compoundfor 40 min at 37° C. in 384-well microtitre plates (10 μl per well finalvolume). The reaction was terminated by the addition of acylation bufferand the amount of SAH produced determined according to manufacturer'sinstructions. Specific inhibition as that inhibited by a highconcentration of tolcapone (10 μM; synthesised at UCB) and allexperiments were validated using a control curve to tolcapone.

The human S-COMT assay was performed as above except that 0.15 ngenzyme/well was incubated with SAM (20 μM final) and dopamine (100 μMfinal) for 15 min at 37° C. and SAH production determined.

HTRF readings were performed using a Perkin Elmer Envision and resultsexpressed as concentration of SAH produced using a standard curve.Results were analysed using non-linear regression to the 4-parameterlogistic equation and pIC50 (−log 10 concentration of drug whichinhibits enzyme activity/SAH production by 50%) determined.

As the data herein indicate, a broad variety of compounds of formula Iwere found effective as COMT inhibitors at low concentrations. pIC₅₀values for exemplary compounds of formula I (see below for compoundnames and structures) are provided in Table 1 below. Any compound with apIC₅₀ superior or equal to 4.5 in this assay, as described above, isdeemed a COMT inhibitor. In the Table 1 below, a single plus (+) isassociated with a pIC₅₀ of from about 4.5 to 6; two plus signs (++) isassociated with a pIC₅₀ of from about great than 6 to 7; and three plussigns (+++) is associated with a pIC₅₀ of above about 7.

TABLE 1 Activity Example range 1 +++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 7 +++8 ++ 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15 ++ 16 +++ 17 ++ 18 +++19 ++ 20 +++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27 +++ 28 +++ 29+++ 30 +++ 31 +++ 32 ++ 33 + 34 ++ 35 ++ 36 +++ 37 ++ 38 ++ 39 +++ 40+++ 41 ++ 42 +++ 43 +++ 44 ++ 45 +++ 46 ++ 47 +++ 48 +++ 49 +++ 50 +++51 +++ 52 +++ 53 +++ 54 +++ 55 ++ 56 +++ 57 ++ 58 +++ 59 +++ 60 ++ 61 ++62 +++ 63 +++ 64 ++ 65 +++ 66 ++ 67 +++ 68 ++ 69 ++ 70 +++ 71 +++ 72 ++73 +++ 74 +++ 75 +++ 76 +++ 77 +++ 78 +++ 79 ++ 80 ++ 81 ++ 82 +++ 83+++ 84 +++ 85 +++ 86 +++ 87 +++ 88 +++ 89 ++ 90 +++ 91 +++ 92 ++ 93 ++94 ++ 95 + 96 ++ 97 ++ 98 ++ 99 ++ 100 ++ 101 +++ 102 +++ 103 ++ 104 +105 ++ 106 + 107 ++ 108 ++ 109 +++ 110 +++ 111 +++ 112 + 113 +++ 114 +115 ++ 116 + 117 ++ 118 ++ 119 ++ 120 + 121 + 122 ++ 123 +++ 124 + 125 +Synthetic Procedures

Exemplary compounds were prepared via several general synthetic routesset forth in the Examples below. Any of the disclosed compounds of thepresent invention can be prepared according to one or more of thesesynthetic routes or specific examples, or via modifications thereofaccessible to the person of ordinary skill in the art.

Example 1: 5-tosylquinolin-8-ol—Method A

Step 1: 5-Iodo-8-((4-methoxybenzyl)oxy)quinoline

To a stirring solution of 5-iodoquinolin-8-ol (4.17 g, 15.38 mmol) inacetonitrile (100 mL), potassium carbonate (4.25 g, 30.8 mmol) wasadded. The solution was stirred at room temperature for 30 min.4-methoxybenzyl chloride (2.51 mL, 18.46 mmol) was added. The solutionwas heated at 80° C. for 4 h. After cooling to room temperature, thesolution was filtered. The filter cake was washed with ethyl acetate.The filtrate was concentrated. The residue was purified by Biotage, andeluted with ethyl acetate/hexanes (0-80%) to give the title compound asan off-white solid (1.37 g, 3.51 mmol, 22.8% yield). MS (ES+) m/z 392.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.95-7.01 (m, 2H) 7.15 (d,J=8.34 Hz, 1H) 7.43-7.49 (m, 2H) 7.67 (dd, J=8.59, 4.29 Hz, 1H)8.06-8.11 (m, 1H) 8.29 (dd, J=8.46, 1.64 Hz, 1H) 8.86 (dd, J=4.04, 1.52Hz, 1H).

Step 2: 8-((4-Methoxybenzyl)oxy)-5-tosylquinoline

To a stirring solution of 5-iodo-8-((4-methoxybenzyl)oxy)quinolone (0.20g, 0.511 mmol) in DMSO (1.5 mL), copper(I) iodide (9.74 mg, 0.051 mmol),sodium (S)-pyrrolidine-2-carboxylate (0.014 g, 0.102 mmol) and sodium4-methylbenzenesulfinate (0.109 g, 0.613 mmol) were added. The solutionwas heated at 90° C. for 24 hrs. Water (2 mL) was added. The precipitatewas isolated by filtration. The crude reaction mixture was purified byBiotage, eluted with ethyl acetate/hexanes (0-80%) to give the titlecompound as an off-white solid (0.047 g, 0.112 mmol, 21.9% yield). MS(ES+) m/z 420.0 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ ppm 3.79-3.86(m, 3H) 5.45 (s, 2H) 6.88-6.99 (m, 2H) 7.16 (d, J=8.59 Hz, 1H) 7.24-7.31(m, 4H) 7.45 (d, J=8.59 Hz, 2H) 7.53 (dd, J=8.84, 4.29 Hz, 1H) 7.81 (d,J=8.34 Hz, 2H) 8.42 (d, J=8.34 Hz, 1H) 9.00 (s, 2H).

Step 3: 5-tosylquinolin-8-ol

8-((4-methoxybenzyl)oxy)-5-tosylquinoline (0.047 g, 0.112 mmol) wasdissolved in TFA (0.863 mL, 11.20 mmol) and stirred at room temperaturefor 1 hour. The solution was concentrated. The residue was purified byrecrystallization in ethyl acetate/hexanes to give the title compound asan off-white solid (30.7 mg, 0.103 mmol, 92% yield). MS (ES+) m/z 300.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 7.27 (d, J=8.34 Hz,1H) 7.35-7.41 (m, 2H) 7.73 (dd, J=8.72, 4.17 Hz, 1H) 7.80-7.86 (m, 2H)8.39 (d, J=8.34 Hz, 1H) 8.89 (dd, J=8.72, 1.64 Hz, 1H) 8.94 (dd, J=4.17,1.64 Hz, 1H).

Example 2: 5-(4-fluorophenyl)sulfonylquinolin-8-ol—Method B

Step 1: Sodium 8-(benzyloxy)quinoline-5-sulfonate

To a stirring solution of 1N aqueous sodium hydroxide (103 mL, 103mmol), 8-hydroxyquinoline-5-sulfonic acid hydrate (10 g, 41.1 mmol) wasadded. The solution was heated to 70° C. After the solution becamehomogeneous, it was cooled to room temperature. Tetrahydrofuran (100 mL)and benzyl chloride (10.41 mL, 90 mmol) were added. The solution washeated at 75° C. overnight. After cooling to room temperature, thesolution was extracted with diethyl ether (2×), then placed in therefrigerator for 4 h. The solid was collected by filtration and dried togive the title compound as a white solid (9.4 g, 67.8% yield). MS (ES+)m/z 314.0 [M−H]0.1H NMR (400 MHz, D₂O) δ ppm 4.63-4.76 (m, 14H) 5.07 (s,2H) 6.90 (d, J=8.34 Hz, 1H) 7.11-7.25 (m, 3H) 7.29 (d, J=7.33 Hz, 2H)7.52 (dd, J=8.84, 4.29 Hz, 1H) 7.84 (d, J=8.34 Hz, 1H) 8.62 (dd, J=4.29,1.26 Hz, 1H) 8.82 (dd, J=8.72, 1.39 Hz, 1H).

Step 2: 8-(Benzyloxy)quinoline-5-sulfonyl Chloride

To a stirring solution of sodium 8-(benzyloxy)quinoline-5-sulfonate(8.54 g, 25.3 mmol) in thionyl chloride (55.4 mL, 760 mmol), DMF (10drops) was added. The solution was heated at 85° C. for 5 h. Thesolution became homogeneous. The solution was concentrated under vacuum.Toluene (100 mL) was added. The solution was evaporated to dryness. Theresidue was dried under vacuum to give the title compound as a slightlycolored solid (9.8 g, 99% yield). MS (ES+) m/z 334.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d6) δ ppm 5.55 (s, 2H) 7.33-7.53 (m, 3H) 7.57-7.76 (m, 3H)8.14 (d, J=8.34 Hz, 1H) 8.22 (dd, J=8.59, 5.31 Hz, 1H) 9.18 (dd, J=5.31,1.52 Hz, 1H) 9.84 (dd, J=8.72, 1.39 Hz, 1H).

Step 3: 8-(Benzyloxy)quinoline-5-sulfonyl Fluoride

To a stirring solution of 8-(benzyloxy)quinoline-5-sulfonyl chloride (2g, 5.99 mmol) in acetonitrile (30 mL), potassium fluoride (1.044 g,17.98 mmol) was added. The solution was stirred at 60° C. for two days.Ethyl acetate (100 mL) was added. The solution was extracted with water(30 mL) (1×), brine (1×), then dried over sodium sulfate. The solutionwas filtered and concentrated. The residue was purified by Biotage,eluted with ethyl acetate/hexanes (0-80%) to give the title compound asa white solid (1.22 g, 3.83 mmol, 63.9% yield). MS (ES+) m/z 227.0[M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ ppm 5.58 (s, 2H) 7.13 (dd,J=8.59, 0.76 Hz, 1H) 7.33-7.46 (m, 3H) 7.49-7.59 (m, 2H) 7.73 (dd,J=8.72, 4.17 Hz, 1H) 8.32 (d, J=8.84 Hz, 1H) 8.83-8.92 (m, 1H) 9.14 (dd,J=4.17, 1.64 Hz, 1H).

Step 4: 8-Benzyloxy-5-(4-fluorophenyl)sulfonyl-quinoline

To a stirring solution of 1-fluoro-4-iodo-benzene (0.209 g, 0.95 mmol)in THF (2 mL) at −78° C., n-butyl lithium (2.5 N, 0.38 mL, 0.95 mmol)was added dropwise into the solution. The solution was stirred at −78°C. for 10 min. It was added dropwise into a stirring solution of8-(benzyloxy)quinoline-5-sulfonyl fluoride (100 mg, 0.315 mmol) in THF(2 mL) at −78° C. The solution was stirred at −78° C. for 1 hour andthen room temperature for 60 min. Methanol (1.0 mL) was added. Thesolution was concentrated. The residue was purified by Biotage, elutedwith ethyl acetate/hexane (0-80%) to give the title compound as a whitesolid (68 mg, 54.8% yield) MS (ES+) m/z 394.0 [M+H]⁺. ¹H NMR (400 MHz,chloroform-d) δ ppm 5.53 (s, 2H) 7.11-7.19 (m, 3H) 7.32-7.45 (m, 3H)7.49-7.59 (m, 3H) 7.90-7.98 (m, 2H) 8.42 (d, J=8.59 Hz, 1H) 8.95 (dd,J=8.72, 1.64 Hz, 1H) 9.03 (dd, J=4.17, 1.64 Hz, 1H).

Step 5: 5-(4-fluorophenyl)sulfonylquinolin-8-ol hydrobromide

To a stirring solution of8-benzyloxy-5-(4-fluorophenyl)sulfonyl-quinoline (30 mg, 0.076 mmol) inacetic acid (0.1 mL), hydrobromic acid (48%, 0.8 mL, 0.076 mmol) wasadded. The solution was stirred at 100° C. overnight. The solution wascooled to 0° C. The solution was diluted with diethyl ether. Theprecipitate was collected by filtration and dried to give the titlecompound as its HBr salt, a white solid (17.7 mg, 60% yield). MS (ES+)m/z 304.0 [M+H]⁺. ¹H NMR (400 MHz, methanol-d4) δ ppm 7.27-7.48 (m, 2H)7.57 (d, J=8.59 Hz, 1H) 8.08-8.34 (m, 3H) 8.73 (d, J=8.34 Hz, 1H) 9.15(br. s., 1H) 9.81 (d, J=9.09 Hz, 1H).

The following compounds were synthesized according Method B:

Preparation Example Name Ar Data Information  3 5-(3,4- dimethylphenyl)sulfonylquinolin- 8-ol

MS (ES+) m/z 314.0 [M + H]⁺. ¹H NMR (400 MHz, methanol-d4) δ ppm 2.31(br. s., 6 H) 7.34 (d, J = 6.32 Hz, 1 H) 7.56 (d, J = 7.83 Hz, 1 H)7.71-7.90 (m, 2 H) 8.23 (d, J = 5.05 Hz, 1 H) 8.71 (d, J = 8.59 Hz, 1 H)9.13 (br. s., 1 H) 9.81 (d, J = 8.59 Hz, 1 H) B, Using 4-iodo-1,2-dimethyl- benzene  4 5-(3,5- dimethylphenyl) sulfonyl- quinolin-8-ol

MS (ES+) m/z 314.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 6H) 7.26 (s, 1 H) 7.32 (d. J = 8.34 Hz, 1 H) 7.57 (s, 2 H) 7.81 (dd, J =8.84, 4.29 Hz, 1 H) 8.43 (d, J = 8.59 Hz, 1 H) 8.95-9.06 (m, 2 H) B,Using 1- bromo-3,5- dimethyl-benzene  5 5-(4-tert- butylphenyl)sulfonylquinolin- 8-ol

MS (ES+) m/z 342.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.23- 1.38(m, 9 H) 7.35-7.46 (m, 1 H) 7.61-7.74 (m, 2 H) 7.85-8.03 (m, 3 H)8.47-8.58 (m, 1 H) 9.07 (br. s., 1 H) 9.16 (d, J = 8.34 Hz, 1 H) B,Using 1- bromo-4-tert- butyl-benzene  6 5-(3- phenylphenyl)sulfonylquinolin- 8-ol

MS (ES+) m/z 362.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.35 (d, J= 8.34 Hz, 1 H) 7.39-7.46 (m, 1 H) 7.46-7.54 (m, 2 H) 7.63-7.72 (m, 3 H)7.87 (dd, J = 8.84, 4.29 Hz, 1 H) 7.95 (d, J = 7.58 Hz, 2 H) 8.18 (s, 1H) 8.55 (d, J = 8.59 Hz, 1 H) 8.99 (d, J = 4.29 Hz, I H) 9.14 (d, J =8.84 Hz, 1H) B, Using 1- bromo-3-phenyl- benzene  7 5-(m- tolylsulfonyl)quinolin-8-ol

MS (ES+) m/z 300.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3H) 7.29 (d, J = 8.34 Hz, 1 H) 7.40-7.51 (m, 2 H) 7.71-7.81 (m, 3 H) 8.42(d, J = 8.34 Hz, 1 H) 8.87-9.01 (m, 2 H) B, Using 1- bromo-3-methyl-benzene  8 5-(3,5- dichlorophenyl) sulfonylquinolin- 8-ol

MS (ES+) m/z 355.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.30 (d, J= 8.59 Hz, 1 H) 7.77-7.83 (m, 1 H) 7.95-7.99 (m, 1 H) 8.03 (d, J = 1.77Hz, 2 H) 8.50 (d, J = 8.34 Hz, 1 H) 8.94-9.01 (m, 2 H) B, Using 1-bromo-3,5- dichloro-benzene  9 5-(4- chlorophenyl) sulfonylquinolin-8-ol

MS (ES+) m/z 320.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.32 (d, J= 8.59 Hz, 1 H) 7.65 (d, J = 8.34 Hz, 2 H) 7.79 (dd, J = 8.84, 4.29 Hz,1 H) 7.98 (d, J = 8.34 Hz, 2 H) 8.45 (d, J = 8.34 Hz, 1 H) 8.90-9.02 (m,2 H) B, Using 1- bromo-4-chloro- benzene 10 5-(2,4- dimethylphenyl)sulfonyl- quinolin-8-ol

MS (ES+) m/z 314.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H) 2.30 (s, 3 H) 7.10-7.19 (m, 1 H) 7.27- 7.37 (m, 2 H) 7.71 (dd, J =8.84, 4.29 Hz, 1 H) 8.07-8.18 (m, 1 H) 8.39 (d, J = 8.34 Hz, 1 H) 8.71(dd, J = 8.84, 1.52 Hz, 1 H) 8.94 (dd, J = 4.17, 1.39 Hz, 1 H) B, Using1- bromo-2,4- dimethyl-benzene 11 5-[4- (trifluoromethyl) phenyl]sulfonyl- quinolin- 8-ol

MS (ES+) m/z 354.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.33 (d, J= 8.34 Hz, 1 H) 7.77 (dd, J = 8.84, 4.29 Hz, 1 H) 7.96 (d, J = 8.34 Hz,2 H) 8.18 (d, J = 8.34 Hz, 2 H) 8.49 (d, J = 8.34 Hz, 1 H) 8.91 (dd, J =8.84, 1.52 Hz, 1 H) 8.97 (dd, J = 4.17, 1.39 Hz, 1 H) B, Using 1-bromo-4- (trifluoromethyl) benzene 12 5-(2- naphthylsulfonyl) quinolin-8-ol

MS (ES+) m/z 336.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.33 (d, J= 8.34 Hz, 1 H) 7.64-7.76 (m, 3 H) 7.78-7.83 (m, 1 H) 7.97-8.03 (m, 1 H)8.04-8.10 (m, 1 H) 8.20-8.25 (m, 1 H) 8.48-8.56 (m, 1 H) 8.82 (d, J =1.77 Hz, 1 H) 8.93 (dd, J = 4.29, 1.52 Hz, 1 H) 8.99-9.07 (m, 1 H) B,Using 2- bromonaphthalene 13 5-[3- (trifluoromethyl) phenyl]sulfonyl-quinolin- 8-ol

MS (ES+) m/z 354.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.32 (d, J= 8.34 Hz, 1 H) 7.76-7.87 (m, 2 H) 8.06 (d, J = 7.33 Hz, 1 H) 8.24-8.31(m, 2 H) 8.51 (d, J = 8.59 Hz, 1 H) 8.93-9.01 (m, 2 H) B, Using 1-bromo-3- (trifluoromethyl) benzene 14 5-(3- chlorophenyl)sulfonylquinolin- 8-ol

MS (ES+) m/z 320.0 [M + H]⁺. B, Using 1- bromo-3-chloro- benzene 155-(3,4- dichlorophenyl) sulfonyl- quinolin-8-ol

MS (ES+) m/z 355.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.31 (d, J= 8.59 Hz, 1 H) 7.77-7.87 (m, 2 H) 7.91-7.96 (m, 1 H) 8.25 (d, J = 2.27Hz, 1 H) 8.48 (d, J = 8.59 Hz, 1 H) 8.94-9.01 (m, 2 H) B, Using 4-bromo-1,2- dichloro-benzene 16 5-(2- pyridylsulfonyl) quinolin-8-ol

MS (ES+) m/z 287.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.34 (d, J= 8.59 Hz, 1 H) 7.66 (ddd, J = 7.64, 4.74, 1.01 Hz, 1 H) 7.81-7.88 (m, 1H) 8.16 (td, J = 7.77, 1.64 Hz, 1 H) 8.31 (dt, J = 8.02, 0.92 Hz, 1 H)8.42 (d, J = 8.34 Hz, 1 H) 8.59-8.64 (m, 1 H) 8.97-9.03 (m, 1 H) 9.14(dd, J = 8.84, 1.52 Hz, 1H) B, Using 2- bromopyridine 17 5-(4-pyridylsulfonyl) quinolin-8-ol

MS (ES+) m/z, 287.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.33 (d, J= 8.34 Hz, 1 H) 7.78 (dd, J = 8.84, 4.04 Hz, 1 H) 7.89-7.95 (m, 2 H)8.48 (d, J = 8.34 Hz, 1 H) 8.81 -8.87 (m, 2 H) 8.89 (dd, J = 8.72, 1.39Hz, 1 H) 8.98 (dd, J = 4.17, 1.14 Hz, 1 H) B, Using 4- iodopyridine 185-(4- methoxyphenyl) sulfonyl- quinolin-8-ol

MS (ES+) m/z 316.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.79 (s, 3H) 7.04-7.12 (m, 2 H) 7.26 (d, J = 8.34 Hz, 1 H) 7.73 (dd, J = 8.72,4.17 Hz, 1 H) 7.86-7.92 (m, 2H) 8.37 (d, J = 8.34 Hz, 1 H) 8.87-8.98 (m,2 H) B, Using 1- bromo-4- methoxy-benzene 19 5-(3- pyridylsulfonyl)quinolin-8-ol

MS (ES+) m/z 287.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.32 (d, J= 8.34 Hz, 1 H) 7.62 (ddd, J = 8.15, 4.86, 0.88 Hz, 1 H) 7.80 (dd, J =8.84, 4.29 Hz, 1 H) 8.35- 8.41 (m, 1 H) 8.49 (d, J = 8.34 Hz, 1 H) 8.82(dd, J = 4.80, 1.52 Hz, 1 H) 8.95-9.04 (m, 2 H) 9.17- 9.21 (m, 1 H) B,Using 3- broinopyridine 20 5-(4-fluono-2- methyl- phenyl) sulfonyl-quinolin-8- ol

MS (ES+) m/z 318.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 7.26 (dd, J = 9.85, 2.53 Hz, 1 H) 7.29-7.34 (m, 1 H) 7.34-7.38 (m, 1H) 7.72 (dd, J = 8.72, 4.17Hz, 1 H) 8.31 (dd, J = 8.84, 5.81 Hz, 1 H)8.40 (d, J = 8.34 Hz, 1 H) 8.70 (dd, J = 8.72, 1.39 Hz, 1 H) 8.95 (dd, J= 4.29, 1.52 Hz, 1 H) B, Using 1- bromo-4-fluoro- 2-methyl-benzene 215-(2- (trifluoromethyl) phenyl] sulfonyl- quinolin- 8-ol

MS (ES+) m/z 314.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.28- 7.39(m, 1 H) 7.67-7.79 (m, 1 H) 7.82-7.97 (m, 2 H) 7.99-8.16 (m, 2 H) 8.32(d, J = 8.59 Hz, 1 H) 8.60-8.70 (m, 1 H) 8.97 (dd, J = 4.29, 1.52 Hz,1H) B, Using 1- bromo-2- (trifluoromethyl) benzene 22 5- (benzene-sulfonyl) quinolin- 8-ol

MS (ES+) m/z 285.9 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.27- 7.34(m, 1 H) 7.54-7.69 (m, 3 H) 7.73-7.80 (m, 1 H) 7.92-8.00 (m, 2 H)8.41-8.47 (m, 1 H) 8.90-9.00 (m, 2 H) B, Using iodobenzene

Example 23: 5-[3-(4-pyridyl)phenyl]sulfonylquinolin-8-ol—Method C

Step 1: 8-Benzyloxy-5-(3-bromophenyl)sulfonyl-quinoline

Following Method B, step 4, and substituting 1-fluoro-4-iodo-benzenewith 1-bromo-3-iodobenzene (0.63 mmol), the title compound was obtainedas a white solid (0.39 g, 21% yield). MS (ES+) m/z 455.0 [M+H]⁺. ¹H NMR(400 MHz, chloroform-d) δ ppm 5.54 (s, 2H) 7.17 (d, J=8.59 Hz, 1H)7.32-7.48 (m, 4H) 7.49-7.62 (m, 3H) 7.63-7.73 (m, 1H) 7.85 (ddd, J=7.83,1.77, 1.01 Hz, 1H) 8.04 (t, J=1.89 Hz, 1H) 8.44 (d, J=8.34 Hz, 1H)8.90-8.99 (m, 1H) 9.04 (dd, J=4.17, 1.64 Hz, 1H).

Step 2: 8-Benzyloxy-5-[3-(4-pyridyl)phenyl]sulfonyl-quinoline

To a stirring solution of8-benzyloxy-5-(3-bromophenyl)sulfonyl-quinoline (92 mg, 0.20 mmol) and4-pyridylboronic acid (37 mg, 0.30 mmol) in dioxane (1 mL), sodiumcarbonate solution (1 M, 0.60 mL, 0.61 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (8.0mg, 0.01 mmol) were added. Water (0.5 mL) was added afterward. Thecontents were heated at 100° C. for 2 h. The reaction mixture wasfiltered and transferred to Gilson HPLC for purification to give thetitle compound as a black solid (62 mg, 67% yield). MS (ES+) m/z 453.0[M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ ppm 5.51 (s, 2H) 7.37-7.46 (m,3H) 7.49-7.58 (m, 2H) 7.63-7.78 (m, 2H) 7.85-7.97 (m, 3H) 8.12 (d,J=7.07 Hz, 1H) 8.24 (s, 1H) 8.55 (d, J=8.59 Hz, 1H) 8.93 (d, J=6.06 Hz,2H) 9.06-9.15 (m, 2H).

Step 3: 5-[3-(4-pyridyl)phenyl]sulfonylquinolin-8-ol dihydrobromide

Following Method B, step 5, and substituting8-benzyloxy-5-(4-fluorophenyl)sulfonyl-quinoline with8-benzyloxy-5-[3-(4-pyridyl)phenyl]sulfonyl-quinoline (0.13 mmol), thetitle compound was obtained as an off-white solid (26 mg, 37% yield). MS(ES+) m/z 363.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.33 (d, J=8.34Hz, 1H) 7.73-7.87 (m, 2H) 8.13-8.20 (m, 1H) 8.23-8.29 (m, 1H) 8.43-8.50(m, 2H) 8.51-8.58 (m, 2H) 8.94-8.99 (m, 1H) 9.00-9.09 (m, 3H).

The following compounds were synthesized using Method C:

Preparation Example Name Ar Data Information 24 5-[3-(3- chloro-4-fluoro- phenyl) phenyl] sulfonyl- quinolin-8-ol

MS (ES+) m/z 413.9 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.28 (d, J= 8.34 Hz, 1 H) 7.50-7.59 (m, 1 H) 7.63-7.70 (m, 1 H) 7.71-7.79 (m, 2 H)7.91-8.03 (m, 3 H) 8.24 (s, 1 H) 8.49 (d, J = 8.59 Hz, 1 H) 8.94 (d, J =4.29 Hz, 1 H) 9.00 (d, J = 8.84 Hz, 1 H) C, Using 3- chloro-4-fluorobenzene- boronic acid 25 5-[3-(5- quinolyl) phenyl] sulfonyl-quinolin-8-ol

MS (ES+) m/z 413.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.32 (d, J= 8.59 Hz, 1 H) 7.73 (d, J = 8.08 Hz, 1 H) 7.81 (dt, J = 8.65, 4.14 Hz,I H) 7.86 (d, J = 7.58 Hz, 1 H) 7.88-7.94 (m, 7 H) 8.02- 8.15 (m, 13 H)8.16-8.24 (m, 2 H) 8.49 (d, J = 8.34 Hz, I H) 8.62 (d, J = 8.34 Hz, 1 H)8.73 (s, 1 H) 9.01 (dd, J = 4.17, 1.39 Hz, 1 H) 9.03-9.10 (m, 1 H) 9.93(s, 1 H) C, Using 5- quinolineboronic acid 26 5-[3-(1H- indazol-4-yl)phenyl] sulfonyl- quinolin- 8-ol

MS (ES+) m/z 402.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.27 (d, J= 7.07 Hz, 1 H) 7.34 (d, J = 8.34 Hz, 1 H) 7.43-7.50 (m, 1 H) 7.62 (d, J= 8.34 Hz, I H) 7.72-7.79(m, 1 H) 7.84 (dd, J = 8.84, 4.29 Hz, 1 H) 7.93(s, 1 H) 8.03 (t, J = 7.71 Hz, 2 H) 8.19 (s, 1 H) 8.54 (d, J = 8.34 Hz,1 H) 8.99 (dd, J = 4.29,1.26 Hz, 1H) 9.11 (d, J = 9.09 Hz, I H) C, Using1H- indazol-4- ylboronic acid

Example 27: 5-[(3-methyl-4-pyridyl)sulfonyl]quinolin-8-ol—Method D

Step 1: 8-benzyloxy-5-[(3-methyl-4-pyridyl)sulfanyl]quinolone

To a stirring solution of 8-benzyloxyquinoline-5-sulfonyl chloride (100mg, 0.30 mmol) in THF (2 mL) with stirring, triphenylphosphine (236 mg,0.90 mmol) was added. The solution was heated at 60° C. for 50 min. Thesolution was cooled to room temperature. Diethyl ether (1.5 mL) wasadded. The precipitate was isolated by filtration and dried. The residuewas dissolved in dioxane (2 mL). Pd₂(dba)₃ (6.8 mg, 0.007 mmol),4-bromo-3-methyl-pyridine (62 mg, 0.36 mmol), DIPEA (0.11 mL, 0.60 mmol)were added. The solution was heated at 110° C. overnight. The solutionwas transferred to Gilson HPLC for purification to provide the titlecompound (TFA salt) as a colorless oil (41.5 mg, 38% yield). MS (ES+)m/z 359.0 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ ppm 2.65 (s, 3H) 5.51(s, 2H) 6.60 (d, J=6.32 Hz, 1H) 7.34 (d, J=8.34 Hz, 1H) 7.38-7.48 (m,3H) 7.53-7.60 (m, 2H) 7.74 (dd, J=8.59, 4.55 Hz, 1H) 7.96 (d, J=8.34 Hz,1H) 8.17 (d, J=6.32 Hz, 1H) 8.53-8.58 (m, 2H) 9.22 (dd, J=4.55, 1.52 Hz,1H).

Step 2:8-benzyloxy-5-[(3-methyl-4-pyridyl)sulfonyl]-1-oxido-quinolin-1-ium

To a stirring solution of8-benzyloxy-5-[(3-methyl-4-pyridyl)sulfanyl]quinolone (70 mg, 0.19 mmol)in methanol (1.5 mL)/water (0.5 mL), oxone monopersulfate (300 mg, 0.49mmol) was added. The solution was stirred at room temperature overnight.The solution was transferred to Gilson HPLC for purification to give thetitle compound as a white solid (26 mg, 32% yield). MS (ES+) m/z 407.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 3H) 5.45 (s, 2H)7.36-7.51 (m, 3H) 7.54-7.62 (m, 3H) 7.67-7.76 (m, 1H) 8.11-8.18 (m, 1H)8.24-8.32 (m, 2H) 8.51 (d, J=8.59 Hz, 1H) 8.61-8.69 (m, 1H) 8.97 (dd,J=4.04, 1.52 Hz, 1H).

Step 3: 8-benzyloxy-5-[(3-methyl-4-pyridyl)sulfonyl]quinolone

To a stirring solution of8-benzyloxy-5-[(3-methyl-4-pyridyl)sulfonyl]-1-oxido-quinolin-1-ium(17.6 mg, 0.04 mmol) in methanol (1 mL), ammonium formate (5.4 mg, 0.087mmol) and Raney nickel (10 mg) were added. The solution was heated at50° C. overnight. The solution was filtered and transferred Gilson HPLCfor purification to give the title compound as a white solid (15 mg, 89%yield). MS (ES+) m/z 391.0 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ ppm2.52 (s, 3H) 5.51 (s, 2H) 7.28 (s, 1H) 7.31-7.38 (m, 1H) 7.38-7.48 (m,3H) 7.52 (dd, J=7.58, 1.52 Hz, 2H) 7.72 (dd, J=8.84, 4.29 Hz, 1H) 8.07(d, J=5.31 Hz, 1H) 8.57 (d, J=8.59 Hz, 1H) 8.64 (s, 1H) 8.77 (d, J=5.31Hz, 1H) 8.90 (dd, J=8.84, 1.26 Hz, 3H) 9.12-9.20 (m, 1H).

Step 4: 5-[(3-methyl-4-pyridyl)sulfonyl]quinolin-8-ol

Following Method B, step 5, substituting8-benzyloxy-5-(4-fluorophenyl)sulfonyl-quinoline with8-benzyloxy-5-[(3-methyl-4-pyridyl)sulfonyl]quinolone (0.038 mmol), thetitle compound was obtained as an off-white solid (5 mg, 31% yield). MS(ES+) m/z 301.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3H)7.33 (d, J=8.59 Hz, 1H) 7.70 (dd, J=8.72, 4.17 Hz, 1H) 8.01 (d, J=5.31Hz, 1H) 8.46 (d, J=8.34 Hz, 1H) 8.59-8.66 (m, 2H) 8.73 (d, J=5.05 Hz,1H) 8.95 (dd, J=4.17, 1.64 Hz, 1H).

Example 28:5-[1-[(2-chlorophenyl)methyl]benzimidazol-4-yl]sulfonylquinolin-8-ol—MethodE

Step 1: N-[(2-chlorophenyl)methyl]-3-fluoro-2-nitro-aniline

To a stirring solution of 2,6-difluoro nitrobenzene (3.83 g, 24 mmol) inacetonitrile (50 mL), 2-chlorobenzylamine (2.9 mL, 24 mmol) and DIPEA(5.1 mL, 28.9 mmol) were added. The solution was stirred at roomtemperature overnight. Water (100 mL) was added and the solution wasextracted with ethyl acetate (3×50 mL). The combined organic solutionwas extracted with water (50 mL), brine (50 mL) and dried over sodiumsulfate. The solution was filtered and concentrated. The residue waspurified by ISCO, eluting with ethyl acetate/hexane (0-20%) to give thetitle compound as a purple solid (2.87 g, 43% yield). MS (ES+) m/z 281.0[M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ ppm 4.56-4.65 (m, 2H) 6.44-6.55(m, 2H) 7.22-7.37 (m, 3H) 7.40-7.52 (m, 1H) 7.62 (br. s., 1H).

Step 2:3-[(8-benzyloxy-5-quinolyl)sulfanyl]-N1-[(2-chlorophenyl)methyl]benzene-1,2-diamine

Following Method D, step 1, and substituting 4-bromo-3-methyl-pyridinewith N-[(2-chlorophenyl)methyl]-3-fluoro-2-nitro-aniline (5.1 mmol),3-[(8-benzyloxy-5-quinolyl)sulfanyl]-N-[(2-chlorophenyl)methyl]-2-nitro-aniline(red solid, 138 mg, 6% yield) and the title compound (white solid, 100mg, 5% yield) were obtained. MS (ES+) m/z 498.0 [M+H]⁺. ¹H NMR (400 MHz,chloroform-d) δ ppm 4.06 (br. s., 2H) 4.44 (br. s., 2H) 5.40-5.49 (m,2H) 6.59-6.66 (m, 1H) 6.71 (t, J=7.83 Hz, 1H) 6.80-6.86 (m, 1H) 6.92 (d,J=8.59 Hz, 1H) 7.12-7.19 (m, 1H) 7.21-7.25 (m, 1H) 7.33-7.64 (m, 9H)8.69 (dd, J=8.59, 1.77 Hz, 1H) 9.03 (dd, J=4.17, 1.89 Hz, 1H).

Step 3:8-benzyloxy-5-[1-[(2-chlorophenyl)methyl]benzimidazol-4-yl]sulfanyl-quinoline

3-[(8-benzyloxy-5-quinolyl)sulfanyl]-N1-[(2-chlorophenyl)methyl]benzene-1,2-diaminewas dissolved in formic acid and heated at 100° C. overnight. Thesolution was concentrated. The residue was purified by Gilson HPLC togive the title compound (TFA salt) as a slightly colored solid (87 mg,87% yield). MS (ES+) m/z 509.0 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δppm 5.45 (s, 2H) 5.57 (s, 2H) 6.70 (d, J=7.83 Hz, 1H) 7.14-7.21 (m, 2H)7.26-7.43 (m, 6H) 7.46-7.52 (m, 2H) 7.55 (d, J=6.82 Hz, 2H) 7.75 (dd,J=8.59, 4.80 Hz, 1H) 7.95-8.02 (m, 1H) 8.80 (s, 1H) 9.11 (d, J=8.59 Hz,1H) 9.23 (d, J=4.04 Hz, 1H).

Step 4:8-benzyloxy-5-[1-[(2-chlorophenyl)methyl]benzimidazol-4-yl]sulfonyl-quinoline

To a stirring solution of8-benzyloxy-5-[1-[(2-chlorophenyl)methyl]benzimidazol-4-yl]sulfanyl-quinoline(80 mg, 0.16 mmol) in dichloromethane (5 mL), mCPBA (77.6 mg, 0.31 mmol)was added. The solution was stirred at room temperature for 1 hour. Thesolution was concentrated. The residue was purified by Gilson HPLC togive the title compound (TFA salt) as a white solid (45.8 mg, 54%yield). MS (ES+) m/z 541.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 5.42(s, 2H) 5.58 (s, 2H) 5.77 (s, 1H) 7.03 (dd, J=7.58, 1.52 Hz, 1H)7.23-7.29 (m, 1H) 7.30-7.53 (m, 6H) 7.54-7.66 (m, 4H) 7.83-7.89 (m, 1H)8.15 (d, J=7.07 Hz, 1H) 8.43 (s, 1H) 8.74 (d, J=8.34 Hz, 1H) 8.86 (dd,J=4.04, 1.52 Hz, 1H) 8.93 (dd, J=8.72, 1.64 Hz, 1H).

Step 5:5-[1-[(2-chlorophenyl)methyl]benzimidazol-4-yl]sulfonylquinolin-8-oldihydrobromide

To a stirring solution of8-benzyloxy-5-[1-[(2-chlorophenyl)methyl]benzimidazol-4-yl]sulfonyl-quinoline(42 mg, 0.078 mmol) in formic acid (0.2 mL), HBr (48%, 0.8 mL) wasadded. The solution was heated at 100° C. for 1 hour. The solution wasconcentrated. The residue was washed with ethyl acetate and dried togive the title compound as white solid (45 mg, 94% yield). MS (ES+) m/z450.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 5.59 (s, 2H) 7.07 (dd,J=7.58, 1.77 Hz, 1H) 7.22-7.30 (m, 1H) 7.31-7.40 (m, 2H) 7.46-7.55 (m,2H) 7.75 (dd, J=8.84, 4.29 Hz, 1H) 7.87 (dd, J=8.21, 0.88 Hz, 1H)8.10-8.18 (m, 1H) 8.53 (s, 1H) 8.71 (d, J=8.59 Hz, 1H) 8.92 (dd, J=4.29,1.52 Hz, 1H) 9.07-9.13 (m, 1H).

Example 29: 5-[2-(p-tolyl)ethylsulfonyl]quinolin-8-ol—Method F

Step 1: 8-benzyloxy-5-[2-(p-tolyl)ethylsulfanyl]quinoline

To a stirring solution of 8-benzyloxyquinoline-5-sulfonyl chloride (100mg, 0.30 mmol) in THF (2 mL) with stirring, triphenylphosphine (236 mg,0.90 mmol) was added. The solution was heated at 60° C. for 30 min. Thesolution was cooled to room temperature. Diethyl ether (1.5 mL) wasadded. The precipitate was isolated by filtration and dried.Tetrahydrofuran (2 mL) was added followed by sodium borohydride (11 mg,0.30 mmol). The solution was stirred at room temperature 30 min. Diethylether (2 mL) was added. The solvents were removed. The residue was driedand then dissolved in THF (2 mL)/DMF (1 mL). Sodium hydride (18 mg, 60%,0.45 mmol) was added followed by 4-Methylphenethyl bromide (59 mg, 0.30mmol). The solution was heated to 80° C. for 3 hrs. The solution wastransferred on Gilson HPLC for purification to give the title compoundas purple solid (36 mg, 31% yield). MS (ES+) m/z 386.0 [M+H]⁺. ¹H NMR(400 MHz, chloroform-d) δ ppm 2.32 (s, 3H) 2.84 (t, J=7.58 Hz, 2H) 3.12(t, J=7.58 Hz, 2H) 5.45 (s, 2H) 6.97-7.03 (m, 2H) 7.05-7.11 (m, 2H)7.22-7.25 (m, 1H) 7.32-7.45 (m, 3H) 7.54-7.61 (m, 2H) 7.79-7.86 (m, 2H)9.16 (d, J=8.84 Hz, 1H) 9.33 (d, J=3.79 Hz, 1H).

Step 2: 8-benzyloxy-5-[2-(p-tolyl)ethylsulfonyl]quinoline

To a stirring solution of8-benzyloxy-5-[2-(p-tolyl)ethylsulfanyl]quinoline (35 mg, 0.09 mmol) indichloromethane (2 mL), mCPBA (46 mg, 0.19 mmol) was added. The solutionwas stirred at room temperature for 60 min. The solution wasconcentrated. The residue was purified by Gilson HPLC to give the titlecompound as white solid (25.6 mg, 65% yield). MS (ES+) m/z 418.0 [M+H]⁺.¹H NMR (400 MHz, chloroform-d) δ ppm 2.06-2.35 (m, 3H) 3.00 (br. s., 2H)3.48 (br. s., 2H) 5.53 (br. s., 2H) 6.82-7.08 (m, 4H) 7.33-7.62 (m, 6H)7.76 (br. s., 1H) 8.33 (d, J=8.59 Hz, 1H) 9.11-9.30 (m, 2H).

Step 3: 5-[2-(p-tolyl)ethylsulfonyl]quinolin-8-ol hydrobromide

To a stirring solution of8-benzyloxy-5-[2-(p-tolyl)ethylsulfonyl]quinolone (24 mg, 0.06 mmol) inacetic acid (0.1 mL), hydrobromic acid (48%, 1 mL) was added. Thesolution was stirred at 100° C. for 4 hrs. The solution was cooled toroom temperature. The solution was diluted with diethyl ether. Theprecipitate was collected by filtration and dried to give the titlecompound as a HBr salt, a white solid (19 mg, 81% yield). MS (ES+) m/z328.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.13-2.22 (s, 3H)2.77-2.88 (m, 2H) 3.62-3.72 (m, 2H) 6.89-7.01 (m, 4H) 7.20-7.29 (m, 1H)7.83 (dd, J=8.59, 4.29 Hz, 1H) 8.11-8.20 (m, 1H) 8.97-9.09 (m, 2H).

The following compounds were synthesized using Method F:

Preparation Example Name R¹ Data Information 30 5- cyclohexylsul-fonylquinolin- 8-ol

MS (ES+) m/z 292.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.25(m, 3 H) 1.26-1.41 (m, 2 H) 1.56 (d, J = 12.13 Hz, 1H) 1.72 (d, J =12.63 Hz, 2 H) 1.84 (d, J = 11.87 Hz, 2 H) 3.15-3.30 (m, 1 H) 7.30 (d, J= 8.34 Hz, 1 H) 7.87 (dd, J = 8.84, 4.29 Hz, 1 H) 8.12 (d, J = 8.34 Hz,1 H) 9.04 (dd, J = 4.29, 1.01 Hz, 1 H) 9.13 (d, J = 8.59 Hz, 1 H) F,Using iodocyclohexane 31 5- cyclopentyl- sulfonylquinolin- 8-ol

MS (ES+) m/z 278.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.60(m, 2 H) 1.60-1.80 (m, 4 H) 1.81-1.92 (m, 2 H) 3.82 (dt, J = 15.16, 7.58Hz, 1 H)7.27 (dd, J = 8.46, 2.15 Hz, 1 H) 7.80-7.92 (m, 1 H) 8.16 (dd, J= 8.08, 1.77 Hz, 1 H) 9.01-9.05 (m, 1 H) 9.09 (br. s., 1 H) F, Usingcyclopentyl iodide 32 5-(p- tolylmethyl- sulfonyl)quinolin- 8-ol

MS (ES+) m/z 314.0 [M + H]⁺ F, Using 4- fluorobenzyl bromide 33 5-ethylsulfonyl- quinolin-8-ol

MS (ES+) m/z 238.0 [M + H]⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.14(m, 12 H) 3.31-3.44 (m, 2 H) 7.26-7.35 (m, 4 H) 7.90 (dd, J = 8.84, 4.29Hz, 4 H) 8.14-8.23 (m, 4 H) 9.06 (dd, J = 4.55, 1.52 Hz, 4 H) 9.11 (dd,J = 8.84, 1.26 Hz, 4 H) F

Example 34: 5-(4-piperidylsulfonyl)quinolin-8-ol—Method G

Step 1: tert-butyl4-[(8-benzyloxy-5-quinolyl)sulfonyl]piperidine-1-carboxylate

Following Method F, steps 1 and 2, and substituting 4-methylphenethylbromide with tert-butyl 4-iodopiperidine-1-carboxylate (12.58 mmol), thetitle compound was obtained as a colorless oil (1.39 g, 25% yield). MS(ES+) m/z 483.0 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ ppm 1.44 (s,9H) 1.60 (s, 2H) 1.67-1.80 (m, 2H) 2.03-2.11 (m, 2H) 3.12 (tt, J=11.91,3.63 Hz, 2H) 5.54 (s, 2H) 7.15 (d, J=8.34 Hz, 1H) 7.33-7.46 (m, 3H)7.50-7.58 (m, 2H) 7.66 (dd, J=8.72, 4.17 Hz, 1H) 8.18 (d, J=8.34 Hz, 1H)9.07-9.19 (m, 2H).

Step 2: 5-(4-piperidylsulfonyl)quinolin-8-ol; 2,2,2-trifluoroacetic acid

To a stirring solution of tert-butyl4-[(8-benzyloxy-5-quinolyl)sulfonyl]piperidine-1-carboxylate (1.03 g,2.1 mmol) in dichloromethane (15 mL), TFA (15 mL) was added. Thesolution was stirred at room temperature for 1 h. The solution wasconcentrated. The residue was dissolved in water (50 mL). Sodiumhydroxide solution (1 N, 10 mL) was added until a white precipitate wasproduced, then extracted with dichloromethane (3×40 mL). The combineddichloromethane solution was extracted with brine (1×40 mL), dried oversodium sulfate, filtered and concentrated to give the title compound(8.2 mg, 24% yield) as an off-white solid. MS (ES+) m/z 383.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.42 (qd, J=12.08, 4.17 Hz, 2H) 1.68 (d,J=10.36 Hz, 2H) 2.29-2.41 (m, 2H) 2.93 (d, J=12.13 Hz, 2H) 3.29-3.42 (m,3H) 5.42 (s, 2H) 7.37-7.49 (m, 3H) 7.53 (d, J=8.59 Hz, 1H) 7.58 (d,J=7.07 Hz, 2H) 7.78 (dd, J=8.84, 4.29 Hz, 1H) 8.17 (d, J=8.59 Hz, 1H)8.98-9.06 (m, 2H).

Step 3: 5-(4-piperidylsulfonyl)quinolin-8-ol

To a stirring solution of tert-butyl4-[(8-benzyloxy-5-quinolyl)sulfonyl]piperidine-1-carboxylate (35 mg,0.065 mmol) in acetic acid (0.05 mL), hydrobromic acid (48%, 0.6 mL) wasadded. The solution was heated at 100° C. for 50 min to give a blacksolution, which was cooled to room temperature and transferred to GilsonHPLC for purification to give the title compound as a TFA salt (8.2 mg,24% yield). MS (ES+) m/z 293.0 [M+H]⁺. ¹H NMR (400 MHz, methanol-d4) δppm 1.28-1.40 (m, 2H) 1.92-2.08 (m, 2H) 2.19 (d, J=13.14 Hz, 2H) 3.01(t, J=11.37 Hz, 2H) 3.23 (q, J=7.33 Hz, 1H) 7.35 (d, J=8.34 Hz, 1H)7.85-7.95 (m, 1H) 8.30 (d, J=8.34 Hz, 1H) 9.04 (d, J=4.55 Hz, 1H) 9.32(d, J=8.34 Hz, 1H).

Example 35:5-[[1-[(4-fluorophenyl)methyl]-4-piperidyl]sulfonyl]quinolin-8-ol

Step 1:8-benzyloxy-5-[[1-[(4-fluorophenyl)methyl]-4-piperidyl]sulfonyl]quinoline

To a stirring mixture of 8-benzyloxy-5-(4-piperidylsulfonyl)quinoline(55 mg, 0.14 mmol) and 4-fluorobenzaldehyde (21 mg, 0.17 mmol) indichloromethane (3 mL) and THF (3 mL), a few drops of acetic acid wasadded. The resulting solution was heated briefly to dissolve thestarting material and cooled to room temperature. Sodiumtriacetoxylborohydride (60.9 mg, 0.29 mmol) was added. The solution wasstirred at room temperature overnight. The solution was concentrated.The residue was purified by Gilson HPLC to give the title compound as awhite solid (TFA salt) (54.6 mg, 77% yield). MS (ES+) m/z 491.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6) δ ppm 1.76-1.93 (m, 2H) 1.99-2.13 (m, 2H) 2.87(br. s., 1H) 3.43 (d, J=12.13 Hz, 2H) 3.65 (t, J=12.25 Hz, 2H) 4.24 (br.s., 2H) 5.43 (s, 2H) 7.23-7.36 (m, 3H) 7.36-7.63 (m, 8H) 7.80 (dd,J=8.72, 4.17 Hz, 1H) 8.19 (d, J=8.34 Hz, 1H) 8.93-9.08 (m, 2H).

Step 2:5-[[1-[(4-fluorophenyl)methyl]-4-piperidyl]sulfonyl]quinolin-8-ol

To a stirring solution of8-benzyloxy-5-[[1-[(4-fluorophenyl)methyl]-4-piperidyl]sulfonyl]quinoline(54 mg, 0.11 mmol) in acetic acid (0.05 mL), hydrobromic acid (48%, 0.6mL) was added. The solution was heated at 100° C. for 60 min. Thesolution was concentrated. The residue was washed with diethyl ether anddried to give the title compound as a white solid, as its hydrobromidesalt (48 mg, 79% yield). MS (ES+) m/z 401.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.81-1.96 (m, 2H) 2.04 (d, J=12.63 Hz, 2H) 2.81-2.96 (m,2H) 3.43 (d, J=12.38 Hz, 2H) 3.57-3.70 (m, 1H) 4.27 (d, J=4.55 Hz, 2H)7.24-7.37 (m, 3H) 7.53 (dd, J=8.59, 5.31 Hz, 2H) 7.89 (dd, J=8.84, 4.29Hz, 1H) 8.14 (d, J=8.59 Hz, 1H) 9.03-9.15 (m, 2H).

Example 36:5-[[1-[(2,3-dichlorophenyl)methyl]-4-piperidyl]sulfonyl]quinolin-8-ol

Step 1:[4-[(8-benzyloxy-5-quinolyl)sulfonyl]-1-piperidyl]-(2,3-dichlorophenyl)methanone

To a stirring mixture of 8-benzyloxy-5-(4-piperidylsulfonyl)quinoline(52 mg, 0.14 mmol), 2,3-dichlorobenzoic acid (39 mg, 0.20 mmol) andDIPEA (0.048 mL, 0.27 mmol) in DMF (1 mL), HBTU (61.9 mg, 0.16 mmol) wasadded. The solution was stirred at room temperature overnight. Thesolution was transferred to Gilson HPLC for purification to give thetitle compound as a white solid, TFA salt (33 mg, 43% yield). MS (ES+)m/z 555 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.68 (m, 2H) 1.79(t, J=13.14 Hz, 1H) 1.93 (t, J=10.36 Hz, 1H) 2.78 (t, J=12.25 Hz, 1H)3.03 (m, 2H) 3.30 (d, J=13.14 Hz, 1H) 3.61-3.76 (m, 1H) 4.56 (d, J=7.33Hz, 1H) 5.43 (s, 2H) 7.29 (dd, J=7.58, 1.52 Hz, 1H) 7.35-7.63 (m, 7H)7.69 (ddd, J=7.89, 4.23, 1.77 Hz, 1H) 7.76-7.89 (m, 1H) 8.19 (dd,J=8.34, 6.32 Hz, 1H) 8.98-9.10 (m, 2H).

Step 2:5-[[1-[(2,3-dichlorophenyl)methyl]-4-piperidyl]sulfonyl]quinolin-8-ol

Following Method G, step 3, substituting tert-butyl4-[(8-benzyloxy-5-quinolyl)sulfonyl]piperidine-1-carboxylate with[4-[(8-benzyloxy-5-quinolyl)sulfonyl]-1-piperidyl]-(2,3-dichlorophenyl)methanone(0.059 mmol), the title compound was obtained as a TFA salt (15 mg, 18%yield). MS (ES+) m/z 451.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.86(d, J=12.38 Hz, 2H) 2.04 (d, J=12.63 Hz, 2H) 3.06 (br. s., 2H) 3.36-3.72(m, 3H) 4.42 (br. s., 2H) 7.27 (d, J=8.59 Hz, 1H) 7.44-7.55 (m, 1H) 7.60(d, J=7.33 Hz, 1H) 7.73-7.94 (m, 2H) 8.10 (d, J=8.84 Hz, 1H) 8.95-9.14(m, 2H).

Example 37: 5-[[1-(4-fluorophenyl)-4-piperidyl]sulfonyl]quinolin-8-ol

Step 1:8-benzyloxy-5-[[1-(4-fluorophenyl)-4-piperidyl]sulfonyl]quinolone

To a stirring mixture of 8-benzyloxy-5-(4-piperidylsulfonyl)quinoline(53 mg, 0.14 mmol), 4-fluoroidobenzene (61 mg, 0.28 mmol), potassiumcarbonate (38 mg, 0.28 mmol), CuI (2.6 mg, 0.014 mmol) in DMSO (1.5 mL),L-proline sodium (3.8 mg, 0.028 mmol) was added. The solution was heatedat 90° C. for 40 hrs. The solution was cooled to room temperature,filtered and purified by Gilson HPLC to give the title compound as itsTFA salt (18 mg, 27% yield). MS (ES+) m/z 477.1 [M+H]⁺. ¹H NMR (400 MHz,methanol-d4) δ ppm 2.00-2.21 (m, 3H) 2.64-2.73 (m, 2H) 3.09 (t, J=12.13Hz, 2H) 3.71 (d, J=11.87 Hz, 2H) 5.57 (s, 2 H) 7.09-7.19 (m, 2H) 7.26(dd, J=8.84, 4.55 Hz, 2H) 7.34-7.47 (m, 4H) 7.54-7.66 (m, 4H) 8.38 (d,J=8.59 Hz, 1H) 9.45 (d, J=8.59 Hz, 1H).

Step 2: 5-[[1-(4-fluorophenyl)-4-piperidyl]sulfonyl]quinolin-8-ol

Following Method G, step 3, substituting tert-butyl4-[(8-benzyloxy-5-quinolyl)sulfonyl]piperidine-1-carboxylate with8-benzyloxy-5-[[1-(4-fluorophenyl)-4-piperidyl]sulfonyl] (0.059 mmol),the title compound was obtained as TFA salt (5.3 mg, 22% yield). MS(ES+) m/z 387.0 [M+H]⁺. ¹H NMR (400 MHz, methanol-d4) δ ppm 2.33-2.47(m, 8H) 3.47-3.90 (m, 1H) 7.30-7.43 (m, 2H) 7.52-7.63 (m, 1H) 7.71 (dd,J=9.22, 4.17 Hz, 2H) 8.31 (dd, J=8.97, 5.18 Hz, 1H) 8.53 (d, J=8.59 Hz,1H) 9.18-9.28 (m, 1H) 9.88 (d, J=8.59 Hz, 1H).

The following compounds were made according the same method:

Preparation Example Name R² Data Information 38 5-[[1-[(2,3-dichlorophen- yl)methyl]-4- piperidyl]sul- fonyl]quinolin- 8-ol

MS (ES+) m/z 451.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (d, J= 12.38 Hz, 2 H) 2.04 (d, J = 12.63 Hz, 2 H) 3.06 (br. s., 2 H) 3.36-3.72 (m, 3 H) 4.42 (br. s., 2 H)7.27 (d, J = 8.59 Hz, 1 H) 7.44-7.55 (m,1 H) 7.60 (d, J = 7.33 Hz, 1 H) 7.73-7.94 (m, 2 H) 8.10 (d, J = 8.84 Hz,1 H) 8.95- 9.14 (m, 2 H) G, Using 2,3- dichlorobenz- aldehyde 395-[[1-(2,3- dimethylphen- yl)-4- piperidyl]sul- fonyl]quinolin- 8-ol

MS (ES+) m/z 397.0 [M + H]⁺. ¹H NMR (400 MHz, methanol-d4) δ ppm 2.16(br. s., 3 H) 2.28 (d, J = 9.35 Hz, 6 H) 3.04 (br. s., 1 H) 7.10 (d, J =8.59 Hz, 3 H) 7.39 (d, J = 8.34 Hz, 1 H) 7.95 (dd, J = 8.72, 4.67 Hz, 1H) 8.36 (d, J = 8.34 Hz, 1 H) 9.07 (dd, J = 4.55, 1.52 Hz, 1 H) 9.45 (d,J = 9.09 Hz, 1 H) G, Using 3- iodo-o-xylene

Example 40:5-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)quinolin-8-ol—Method I

Step 1: 8-hydroxyquinoline-5-sulfonyl chloride

8-hydroxyquinoline-5-sulfonic acid hydrate (3.11 g, 12.8 mmol) wassuspended in thionyl chloride (10 mL, 137 mmol) and DMF (49.5 μL, 0.64mmol). The suspension was stirred at 70° C. for 14 h. After cooling, thesolvent was removed in vacuo followed by addition of toluene and furthersolvent removal in vacuo (2×) to give 8-hydroxyquinoline-5-sulfonylchloride (3.08 g, 12.6 mmol, 98% yield) as a yellow solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 9.80 (dd, J=8.72, 1.39 Hz, 1H) 9.10 (dd, J=5.31,1.52 Hz, 1H) 8.15 (dd, J=8.84, 5.30 Hz, 1H) 8.09 (d, J=8.08 Hz, 1H) 7.38(d, J=8.08 Hz, 1H).

Step 2: 5-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)quinolin-8-ol

To a solution of 1,2,3,4-tetrahydroisoquinoline (109 mg, 103 μL, 0.41mmol) in DCM (2 mL) was added triethylamine (125 mg, 172 μL, 1.23 mmol).To this solution was added 8-hydroxyquinoline-5-sulfonyl chloride (100mg, 0.41 mmol) in portions over 1 h. The reaction mixture was allowed tostir overnight, then the balance of the material was added over 1 h.After stirring 1 h after final addition of sulfonyl chloride, thereaction mixture was applied directly to a 10 g silica gel cartridge andpurified by automated normal-phase chromatography (2-20% MeOH/DCM). Theproduct-containing fractions were combined and the solvent removed invacuo to give 5-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)quinolin-8-ol(33 mg, 0.097 mmol, 24% yield) as a tan solid. MS (ES+) m/z 341.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (dd, J=8.72, 1.64 Hz, 1H)8.96 (dd, J=4.30, 1.52 Hz, 1H) 8.18 (d, J=8.34 Hz, 1H) 7.74 (dd, J=8.72,4.17 Hz, 1H) 7.21 (d, J=8.59 Hz, 1H) 7.11 (d, J=3.03 Hz, 3H) 7.05-7.09(m, 1H) 4.30 (s, 2H) 3.43 (t, J=5.94 Hz, 2H) 2.78 (t, J=5.94 Hz, 2H).

Example 41: 5-(4-phenylpiperazin-1-yl)sulfonylquinolin-8-ol—Method J

To a suspension of 8-hydroxyquinoline-5-sulfonyl chloride (50 mg, 0.21mmol) in DCM (1 mL) was added N,O-bis(trimethylsilyl)acetamide (63 mg,75 μL, 0.31 mmol). The contents were stirred 15 min at room temperature,then a solution of 1-phenylpiperazine (50 mg, 47 μL, 0.31 mmol) andtriethylamine (31 mg, 43 μL, 0.31 mmol) in DCM (1 mL) was added. Theresulting mixture was stirred at room temperature for 2 h. The reactionmixture was treated with 2 mL saturated NaHCO₃, agitated vigorously,then eluted through a phase separator tube. The collected DCM fractionwas applied directly to a 10 g silica gel cartridge and purified byautomated normal-phase chromatography (2-25% MeOH/CH₂Cl₂). Theproduct-containing fractions were combined and the solvent removed invacuo to give 5-(4-phenylpiperazin-1-yl)sulfonylquinolin-8-ol (20 mg,0.049 mmol, 24% yield) as a light green solid. MS (ES+) m/z 370.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (dd, J=8.84, 1.52 Hz, 1H)8.99 (dd, J=4.04, 1.52 Hz, 1H) 8.13 (d, J=8.34 Hz, 1H) 7.79 (dd, J=8.84,4.04 Hz, 1H) 7.21-7.26 (m, 2H) 7.18 (dd, J=8.72, 7.20 Hz, 2H) 6.87 (dd,J=8.84, 1.01 Hz, 2H) 6.75-6.81 (m, 1H) 3.48-3.54 (m, 1H) 3.07-3.16 (m,7H).

Example 42:8-hydroxy-N-[(3-methoxyphenyl)methyl]-N-methyl-quinoline-5-sulfonamide—MethodK

Step 1: 8-fluoroquinoline-5-sulfonyl chloride

8-fluoroquinoline (2.24 g, 15.22 mmol) was added dropwise with stirringto chlorosulfonic acid (10 mL, 150.45 mmol). The resulting mixture wasstirred at 100° C. for 16 h, 125° C. for 6 h, then 100° C. for 26 h.Reaction complete by LCMS. Carefully added the reaction mixture dropwiseto ice-water with stirring. Collected solid by filtration and air-driedto give 8-fluoroquinoline-5-sulfonyl chloride (2.61 g, 70% yield) as awhite solid. MS (ES+) m/z 246.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm9.36 (d, J=8.59 Hz, 1H) 9.04 (d, J=3.28 Hz, 1H) 8.02 (dd, J=8.08, 5.31Hz, 1H) 7.82 (dd, J=8.72, 4.42 Hz, 1H) 7.62 (dd, J=10.61, 8.08 Hz, 1H).

Step 2:8-tert-butoxy-N-[(3-methoxyphenyl)methyl]-N-methyl-quinoline-5-sulfonamide

8-fluoroquinoline-5-sulfonyl chloride (50 mg, 0.20 mmol) was dissolvedin THF (1 mL). To this solution was added a solution of3-methoxy-N-methylbenzylamine (31 mg, 36 μL, 0.20 mmol) and DIPEA (70.9μL, 0.41 mmol) in THF (0.50 mL). The resulting mixture was stirred atroom temperature for 5 min. Complete conversion to intermediatefluoroquinoline sulfonamide by LCMS. Added potassium t-butoxide (68.5mg, 0.61 mmol) and stirred at ambient temperature overnight. Thereaction mixture was treated with 2 mL water and 2 mL DCM, agitatedvigorously, then eluted through a phase separator tube. The collectedDCM fraction was purified directly by automated normal-phasechromatography (12-100% EtOAc/hexanes, 10 g silica gel cartridge). Theproduct-containing fractions were combined and the solvent removed invacuo to give8-tert-butoxy-N-[(3-methoxyphenyl)methyl]-N-methyl-quinoline-5-sulfonamide(28 mg, 0.068 mmol, 33% yield) as a colorless oil. MS (ES+) m/z 415.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.02 (dd, J=4.04, 1.52 Hz, 1H)8.95 (dd, J=8.84, 1.77 Hz, 1H) 8.17 (d, J=8.34 Hz, 1H) 0.74 (dd, J=8.72,4.17 Hz, 1H) 7.54 (d, J=8.34 Hz, 1H) 7.20-7.26 (m, 1H) 6.79-6.86 (m, 2H)6.71-6.74 (m, 1H) 4.29 (s, 2H) 3.64 (s, 3H) 2.66 (s, 3H) 1.54 (s, 9H).

Step 3:8-hydroxy-N-[(3-methoxyphenyl)methyl]-N-methyl-quinoline-5-sulfonamide

4M HCl in dioxane (0.5 mL, 2 mmol) was added to8-tert-butoxy-N-[(3-methoxyphenyl)methyl]-N-methyl-quinoline-5-sulfonamide(25 mg, 0.060 mmol) and stirred at ambient temperature for 2 h. Completeconversion to product by LCMS. Added Et₂O, collected solid byfiltration, washed with Et₂O and air-dried to give8-hydroxy-N-[(3-methoxyphenyl)methyl]-N-methyl-quinoline-5-sulfonamidehydrochloride (19.2 mg, 0.049 mmol, 81% yield) as a yellow solid. MS(ES+) m/z 359.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.00-9.11 (m,2H) 8.18 (d, J=8.34 Hz, 1H) 7.85 (dd, J=8.84, 4.29 Hz, 1H) 7.19-7.29 (m,2H) 6.78-6.87 (m, 2H) 6.72 (s, 1H) 4.24 (s, 2H) 3.65 (s, 3H) 2.61 (s,3H).

Example 43: 5-(4-benzylpiperazin-1-yl)sulfonylquinolin-8-ol—Method L

Step 1:2-[[5-(4-benzylpiperazin-1-yl)sulfonyl-8-quinolyl]oxy]ethyl-trimethyl-silane

8-fluoroquinoline-5-sulfonyl chloride (50 mg, 0.20 mmol) was suspendedin THF (1 mL). To this suspension was added DIPEA (70.9 μL, 0.41 mmol),followed by 1-benzylpiperazine (36 mg, 36 μL, 0.20 mmol). The resultingmixture was stirred at room temperature for 15 min. A suspension of2-(trimethylsilyl)ethanol (0.15 mL, 1.02 mmol) and 60% sodium hydride(40.71 mg, 1.02 mmol) in THF (1 mL) were added and the resulting mixturewas stirred at ambient temperature for 30 min. Water was added and themixture extracted with CHCl₃. The organic layer was concentrated invacuo, and the residue purified by automated normal-phase chromatography(0-100% EtOAc/hexanes, 4 g silica gel cartridge). The product-containingfractions were combined, and the solvent removed in vacuo to give2-[[5-(4-benzylpiperazin-1-yl)sulfonyl-8-quinolyl]oxy]ethyl-trimethyl-silane(75.6 mg, 0.156 mmol, 77% yield) as a colorless syrup. MS (ES+) m/z484.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (dd, J=8.84, 1.52 Hz,1H) 9.02 (dd, J=4.04, 1.52 Hz, 1H) 8.19 (d, J=8.59 Hz, 1H) 7.56 (dd,J=8.84, 4.04 Hz, 1H) 7.20-7.31 (m, 5H) 7.05 (d, J=8.59 Hz, 1H) 4.40-4.47(m, 2H) 3.45 (s, 2H) 3.13 (br. s., 4H) 2.43-2.49 (m, 4H) 1.41-1.47 (m,2H) 0.13-0.17 (m, 9H).

Step 2: 5-(4-benzylpiperazin-1-yl)sulfonylquinolin-8-ol

To a solution of2-[[5-(4-benzylpiperazin-1-yl)sulfonyl-8-quinolyl]oxy]ethyl-trimethyl-silane(53.4 mg, 0.11 mmol) in DMF (0.50 mL) was added cesium fluoride (50.3mg, 0.33 mmol). The contents were stirred at 60° C. for 3 h. Thereaction mixture was cooled to room temperature and diluted with EtOAc.The resulting mixture was then washed with water (3×), brine, dried withMgSO₄, filtered and the solvent removed in vacuo to give5-(4-benzylpiperazin-1-yl)sulfonylquinolin-8-ol (23.6 mg, 0.062 mmol,56% yield) as a beige solid. MS (ES+) m/z 384.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d6) δ ppm 11.11 (br. s, 1H) 8.98 (dd, J=6.44, 1.14 Hz, 2H) 8.07 (d,J=8.59 Hz, 1H) 7.73-7.78 (m, 1H) 7.17-7.29 (m, 6H) 3.41 (s, 2H) 2.99(br. s., 4H) 2.36 (br. s., 4H).

The following compounds were synthesized using one of the previousmethods:

Ex. —NR²R³ Name Data Prep Info 44

8-hydroxy-N-(4- methylbenzyl)quinoline- 5-sulfonamide MS (ES+) m/z 329.0[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.93-9.00 (m, 2 H) 8.29 (br.s., 1 H) 8.03 (d, J = 8.34 Hz, 1 H) 7.69-7.76 (m, 1 H) 7.09 (d, J = 8.34Hz, 1 H) 6.88- 6.97 (m, 5 H) 3.90 (s, 2 H) 2.18 (s, 3 H) I 45

N-benzyl-8-hydroxy- N-methylquinoline-5- sulfonamide MS (ES+) m/z 329.0[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.07 (br. s., 1 H) 9.01 (d, J= 2.02 Hz, 1 H) 9.00 (s, 1 H) 8.15 (d, J = 8.34 Hz, 1 H) 7.78-7.82 (m, 1H) 7.28- 7.36 (m, 3 H) 7.23-7.26 (m, 2 H) 7.21 (d, J = 8.59 Hz, 1 H)4.27 (s, 2 H) 2.59 (s, 3 H) I 46

8-hydroxy-N-(4- methylphenyl)-N- methylquinoline-5- sulfonamide MS (ES+)m/z 329.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (br. s., 1 H)8.89 (dd, J = 4.04, 1.52 Hz, 1 H) 8.34 (dd, J = 8.84, 1.52 Hz, 1 H) 7.98(d, J = 8.34 Hz, 1 H) 7.47 (dd, J = 8.84, 4.29 Hz, 1 H) 7.17 (d, J =8.34 Hz, 1 H) 7.06 (d, J = 7.83 Hz, 2 H) 6.92-6.97 (m, 2 H) 3.09 (s, 3H) 2.26 (s, 3 H) I 47

5-isoindolin-2- ylsulfonylquinolin-8- ol MS (ES+) m/z 327.0 [M + H]⁺ ¹HNMR (400 MHz, DMSO-d6) δ ppm 11.09 (br. s., 1 H) 9.09 (dd, J = 8.59,1.52 Hz, 1 H) 8.98 (dd, J = 4.04, 1.52 Hz, 1 H) 8.16 (d, J = 8.34 Hz, 1H) 7.79 (dd, J = 8.84, 4.04 Hz, 1 H) 7.24 (br. s, 4 H) 7.20 (d, J = 8.34Hz, 1 H) 4.58 (s, 4 H) I 48

8-hydroxy-N-methyl- N-phenethyl- quinoline-5- sulfonamide MS (ES+) m/z343.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (dd, J = 4.29, 1.52Hz, 2 H) 8.78 (dd, J = 8.84, 1.52 Hz, 2 H) 8.08 (d, J = 8.34 Hz, 2 H)7.69 (dd, J = 8.84, 4.04 Hz, 2H) 7.07-7.22 (m, 11 H) 3.29-3.36 (m, 4 H)2.71-2.78 (m, 9 H) I 49

N-[(4- fluorophenyl)methyl]- 8-hydroxy-N-methyl- quinoline-5-sulfonamide MS (ES+) m/z 347.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm8.97-9.03 (m, 2 H) 8.14 (d, J = 8.34 Hz, 1 H) 7.76-7.83 (m, 1 H)7.26-7.33 (m, 2 H) 7.12-7.24 (m, 3 H), 4.26 (s, 2 H) 2.59 (s, 3 H) I 50

8-hydroxy-N-methyl- N-[(1R)-1- phenylethyl]quinoline- 5-sulfonamide MS(ES+) m/z 343.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.97-9.04 (m, 1H) 8.89-8.96 (m, 1 H) 8.18 (d, J = 8.34 Hz, 1 H) 7.78 (dd, J = 8.72,4.17 Hz, 1 H) 7.17-7.32 (m, 6 H) 5.19 (q, J = 7.33 Hz, 1 H) 2.51 (s, 3H) 1.27 (d, J = 7.07 Hz, 3 H) I 51

8-hydroxy-N-methyl- N-[(1S)-1- phenylethyl]quinoline- 5-sulfonamide MS(ES+) m/z 343.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (dd, J =4.17, 1.14 Hz, 1 H) 8.92 (dd, J = 8.84, 1.01 Hz, 1 H) 8.18 (d, J = 8.34Hz, 1 H) 7.78 (dd, J = 8.84, 4.29 Hz, 1 H) 7.17-7.32 (m, 6 H) 5.19 (q, J= 6.65 Hz, 1 H) 2.51 (s, 3 H) 1.27 (d, J = 7.07 Hz, 3 H) I 52

N-[(2- fluorophenyl)methyl]- 8-hydroxy-N-methyl- quinoline-5-sulfonamide MS (ES+) m/z 347.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm11.09 (br. s., 1 H) 8.95-9.01 (m, 2 H) 8.15 (d, J = 8.59 Hz, 1 H) 7.77(dd, J = 8.72, 4.17 Hz, 1 H) 7.31-7.39 (m, 2 H) 7.14-7.23 (m, 3 H) 4.34(s, 2 H) 2.63 (s, 3 H) I 53

N-[(3- chlorophenyl)methyl]- 8-hydroxy-N-methyl- quinoline-5-sulfonamide MS (ES+) m/z 363.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm11.13 (br. s., 1 H) 8.95-9.04 (m, 2 H) 8.15 (d, J = 8.34 Hz, 1 H) 7.79(dd, J = 8.72, 4.17 Hz, 1 H) 7.18-7.41 (m, 5 H) 4.29 (s, 2 H) 2.63 (s, 3H) I 54

8-hydroxy-N-methyl- N-(3- pyridylmethyl)quinoline- 5-sulfonamide MS(ES+) m/z 330.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.97-9.02 (m, 2H) 8.49 (dd, J = 4.80, 1.77 Hz, 1 H) 8.43 (d, J = 1.77 Hz, 1 H) 8.16 (d,J = 8.59 Hz, 1 H) 7.79 (dd, J = 8.72, 4.17 Hz, 1 H) 7.67 (dt, J = 7.89,1.99 Hz, 1 H) 7.37 (ddd, J = 7.83, 4.80, 0.76 Hz, 1 H) 7.22 (d, J = 8.34Hz, 1 H) 4.33 (s, 2 H) 2.63 (s, 3H) I 55

8-hydroxy-N-methyl- N-(2- naphthylmethyl)quinoline- 5-sulfonamide MS(ES+) m/z 379.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (dd, J =8.72, 1.39 Hz, 1 H) 9.01 (dd, J = 4.04, 1.52 Hz, 1 H) 8.23 (d, J = 8.34Hz, 1 H) 8.17 (d, J = 8.34 Hz, 1 H) 7.95 (d, J = 7.33 Hz, 1 H) 7.90 (t,J = 4.80 Hz, 1 H) 7.78 (dd, J = 8.97, 4.17 Hz, 1 H) 7.42-7.57 (m, 4 H)7.26 (d, J = 8.34 Hz, 1 H) 4.65 (s, 2 H) 2.50 (s, 3 H) I 56

N-benzyl-N-ethyl-8- hydroxy-quinoline-5- sulfonamide MS (ES+) m/z 379.0[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (br. s., 1 H) 9.00 (dd, J= 4.04, 1.52 Hz, 1 H) 8.91 (dd, J = 8.84, 1.52 Hz, 1 H) 8.15 (d, J =8.34 Hz, 1 H) 7.79 (dd, J = 8.72, 4.17 Hz, 1 H) 7.16-7.36 (m, 6 H) 4.42(s, 2 H) 3.17 (q, J = 7.07 Hz, 2H) 0.82 (t, J = 7.07 Hz, 3 H) I 57

N-benzyl-N-(2- dimethylaminoethyl)- 8-hydroxy-quinoline- 5-sulfonamideMS (ES+) m/z 386.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (dd, J= 4.04, 1.52 Hz, 2 H) 8.92 (dd, J = 8.72, 1.64 Hz, 1 H) 8.18 (d, J =8.34 Hz, 1 H) 7.79 (dd, J = 8.72, 4.17 Hz, 1 H) 7.19-7.32 (m, 5 H) 7.17(d, J = 8.34 Hz, 1 H) 4.47 (s, 2 H) 3.17 (t, J = 6.95 Hz, 2 H) 2.06 (t,J = 7.07 Hz, 2 H) 1.88 (s, 6 H) I 58

5-(2-phenylpyrrolidin- 1-yl)sulfonylquinolin- 8-ol MS (ES+) m/z 355.0[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.93 (dd, J = 4.17, 1.39 Hz, 1H) 8.86 (dd, J = 8.84, 1.26 Hz, 1 H) 8.02 (d, J = 8.59 Hz, 1 H) 7.68(dd, J = 8.84, 4.04 Hz, 1 H) 7.11 (s, 5 H) 7.08 (d, J = 8.34 Hz, 1 H)4.80 (dd, J = 8.21, 4.67 Hz, 1 H) 3.46-3.55 (m, 2 H) 2.06- 2.17 (m, 1 H)1.77-1.89 (m, 1 H) 1.61- 1.74 (m, 2 H) J 59

5-pyrrolidin-1- ylsulfonylquinolin-8- ol MS (ES+) m/z 279.0 [M + H]⁺ ¹HNMR (400 MHz, DMSO-d6) δ ppm 11.02 (br. s., 1 H) 9.04 (dd, J = 8.84,1.52 Hz, 1 H) 8.98 (dd, J = 4.04, 1.52 Hz, 1 H) 8.09 (d, J = 8.34 Hz, 1H) 7.77 (dd, J = 8.72, 4.17 Hz, 1 H) 7.20 (d, J = 8.34 Hz, 1 H)3.13-3.20 (m, 4 H) 1.70 (dt, J = 6.51, 3.44 Hz, 4 H) J 60

5-(4-methylpiperazin- 1-yl)sulfonylquinolin- 8-ol MS (ES+) m/z 308.0[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.95-9.00 (m, 2 H) 8.08 (d, J =8.34 Hz, 1 H) 7.75-7.79 (m, 1 H) 7.21 (d, J = 8.34 Hz, 1 H) 2.99 (br.s., 4 H) 2.28 (t, J = 4.67 Hz, 4 H) 2.10 (s, 3 H) J 61

5-[(2-phenyl-1- piperidyl)sulfonyl] quinolin-8-ol MS (ES+) m/z 369.0[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (dd, J = 4.29, 1.52 Hz, 1H) 8.94 (dd, J = 8.84, 1.52 Hz, 1 H) 8.19 (d, J = 8.34 Hz, 1 H) 7.80(dd, J = 8.84, 4.04 Hz, 1 H) 7.27-7.34 (m, 4 H) 7.19-7.26 (m, 1 H) 7.16(d, J = 8.34 Hz, 1 H) 5.25 (d, J = 3.54 Hz, 1 H) 3.69 (d, J = 12.88 Hz,1 H) 2.92-3.01 (m, 1 H) 2.21 (d, J = 11.37 Hz, 1 H) 1.50 (ddd, J =18.13, 9.54, 4.93 Hz, 1 H) 1.30-1.42 (m, 2 H) 1.09-1.19 (m, 1 H)0.82-1.00 (m, 1 H) J 62

5-(3-(4- fluorophenyl)pyrrolidin- 1- yl)sulfonylquinolin-8- ol MS (ES+)m/z 373.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (dd, J = 8.72,1.64 Hz, 1 H) 8.99 (dd, J = 4.17, 1.64 Hz, 1 H) 8.13 (d, J = 8.34 Hz, 1H) 7.77 (dd, J = 8.84, 4.29 Hz, 1 H) 7.16-7.23 (m, 3 H) 7.02-7.09 (m, 2H) 3.68 (dd, J = 9.60, 7.58 Hz, 1 H) 3.45 (td, J = 8.97, 3.28 Hz, 1 H)3.23-3.31 (m, 2 H) 3.04- 3.11 (m, 1 H) 2.14-2.24 (m, 1 H) 1.79- 1.91 (m,1 H) J 63

5-(piperidin-1- yl)sulfonylquinolin-8- ol MS (ES+) m/z 293.0 [M + H]⁺ ¹HNMR (400 MHz, DMSO-d6) δ ppm 8.96-9.02 (m, 2 H) 8.07 (d, J = 8.34 Hz, 1H) 7.77 (dd, J = 8.84, 4.29 Hz, 1 H) 7.21 (d, J = 8.34 Hz, 1 H) 2.96-3.01 (m, 4 H) 1.47 (d, J = 4.80 Hz, 4 H) 1.35 (d, J = 4.55 Hz, 2 H) J 64

5-(4-morpholin-1- yl)sulfonylquinolin-8- ol MS (ES+) m/z 295.0 [M + H]⁺¹H NMR (400 MHz, DMSO-d6) δ ppm 8.98-9.04 (m, 2 H) 8.10 (d, J = 8.34 Hz,1 H) 7.79 (dd, J = 8.59, 4.29 Hz, 1 H) 7.23 (d, J = 8.34 Hz, 1 H) 3.54-3.60 (m, 4 H) 2.94-2.99 (m, 4 H) J 65

N-[(4- (trifluoromethyl)phenyl) methyl]-8-hydroxy- N-methyl-quinoline-5-sulfonamide MS (ES+) m/z 397.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm11.10 (br. s., 1 H) 8.98-9.02 (m, 2 H) 8.16 (d, J = 8.34 Hz, 1 H) 7.77-7.82 (m, 1 H) 7.72 (d, J = 8.34 Hz, 2 H) 7.50 (d, J = 8.08 Hz, 2 H) 7.22(d, J = 8.59 Hz, 1 H) 4.40 (s, 2 H) 2.64 (s, 3H) J 66

N-ethyl-8-hydroxy-N- (4- pyridylmethyl)quinoline- 5-sulfonamide MS (ES+)m/z 344.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (dd, J = 4.04,1.52 Hz, 1 H) 8.88-8.92 (m, 1 H) 8.46-8.48 (m, 2 H) 8.15 (d, J = 8.34Hz, 1 H) 7.79 (dd, J = 8.72, 4.17 Hz, 1 H) 7.22-7.25 (m, 2 H) 7.18 (d, J= 8.59 Hz, 1 H) 4.49 (s, 2 H) 3.22 (q, J = 7.24 Hz, 2 H) 0.84 (t, J =7.20 Hz, 3 H) J 67

5-(6,8-dihydro-5H- 1,7-naphthyridin-7- ylsulfonyl)quinolin-8- ol MS(ES+) m/z 342.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.94-9.01 (m, 2H) 8.32 (dd, J = 4.80, 1.52 Hz, 1 H) 8.20 (d, J = 8.34 Hz, 1 H) 7.76(dd, J = 8.72, 4.17 Hz, 1 H) 7.51 (d, J = 6.32 Hz, 1 H) 7.22 (d, J =8.34 Hz, 1 H) 7.18 (dd, J = 7.71, 4.67 Hz, 1 H) 4.29 (s, 2H) 3.48 (t, J= 5.81 Hz, 2 H) 2.80 (t, J = 5.81 Hz, 2 H) J 68

N,N-diethyl-8- hydroxy-quinoline-5- sulfonamide MS (ES+) m/z 281.0 [M +H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.98 (dd, J = 4.04, 1.52 Hz, 1 H)8.86 (dd, J = 8.84, 1.52 Hz, 1 H) 8.08 (d, J = 8.34 Hz, 1 H) 7.78 (dd, J= 8.84, 4.04 Hz, 1 H) 7.17 (d, J = 8.34 Hz, 1H) 3.25 (q, J = 7.07 Hz, 6H) 0.98 (t, J = 7.07 Hz, 8 H) J 69

5-[4-(5-chloro-2- pyridyl)piperazin-1- yl]sulfonylquinolin-8- ol MS(ES+) m/z 405.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.13 (br. s.,1 H) 9.02 (dd, J = 8.72, 1.64 Hz, 1 H) 8.97-8.99 (m, 1 H) 8.11 (d, J =8.59 Hz, 1 H) 8.06 (d, J = 2.53 Hz, 1 H) 7.78 (dd, J = 8.84, 4.04 Hz, 1H) 7.57 (dd, J = 9.10, 2.78 Hz, 1 H) 7.22 (d, J = 8.59 Hz, 1 H) 6.82 (d,J = 9.09 Hz, 1 H) 3.53 (d, J = 4.29 Hz, 4 H) 3.08 (d, J = 4.55 Hz, 4 H)K 70

5-[(3R,4R)-3,4- difluoropyrrolidin-1- yl]sulfonylquinolin-8- ol MS (ES+)m/z 315.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.98-9.05 (m, 2 H)8.14 (d, J = 8.34 Hz, 1 H) 7.80 (dd, J = 8.84, 4.29 Hz, 1 H) 7.21 (d, J= 8.34 Hz, 1 H) 5.19- 5.38 (m, 2 H) 3.44-3.65 (m, 4 H) K 71

5-[2-(o- tolyl)pyrrolidin-1- yl]sulfonylquinolin-8- ol MS (ES+) m/z369.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.92-9.00 (m, 2 H) 8.06(d, J = 8.34 Hz, 1 H) 7.74 (dd, J = 8.08, 4.04 Hz, 1 H) 7.11 (d, J =8.34 Hz, 1 H) 6.94- 7.06 (m, 3 H) 6.84 (d, J = 6.57 Hz, 1 H) 4.95 (d, J= 4.55 Hz, 1 H) 3.50-3.61 (m, 2 H) 2.21 (s, 3 H) 2.15 (d, J = 6.06 Hz,1H) 1.66-1.87 (m, 2 H) 1.55 (d, J = 6.82 Hz, 1H) K 72

5-[2-(3- pyridyl)pyrrolidin-1- yl]sulfonylquinolin-8- ol MS (ES+) m/z356.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.98-9.05 (m, 2 H) 8.79(br. s., 1 H) 8.72 (br. s., 1 H) 8.40 (d, J = 8.08 Hz, 1 H) 8.14 (dd, J= 8.21, 3.66 Hz, 1 H) 7.81-7.89 (m, 2 H) 7.25 (dd, J = 8.34, 3.54 Hz, 1H) 4.95-5.02 (m, 1 H) 3.68 (d, J = 6.32 Hz, 1 H) 3.45-3.54 (m, 1 H) 2.21(br. s., 1 H) 1.90 (br. s., 1 H) 1.81 (br. s., 1 H) 1.70 (br. s., 1 H) K73

5-[(4-phenyl-1- piperidyl)sulfonyl] quinolin-8-ol MS (ES+) m/z 369.0[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (d, J = 8.84 Hz, 1 H) 9.04(br. s., 1 H) 8.16 (d, J = 8.34 Hz, 1 H) 7.88 (br. s., 1 H) 7.22-7.36(m, 3 H) 7.10- 7.21 (m, 3 H) 3.81 (d, J = 10.11 Hz, 2 H) 2.45 (br. s., 3H) 1.78 (d, J = 11.12 Hz, 2 H) 1.58 (d, J = 9.85 Hz, 2 H) K 74

5-[2-(4- fluorophenyl)pyrrolidin- 1- yl]sulfonylquinolin-8- ol MS (ES+)m/z 373.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.97 (br. s, 1 H)8.94 (dd, J = 4.30, 1.52 Hz, 1 H) 8.84 (dd, J = 8.84, 1.52 Hz, 1 H) 8.01(d, J = 8.34 Hz, 1 H)7.69 (dd, J = 8.72, 4.17 Hz, 1 H) 7.05-7.17 (m, 3H) 6.85-6.96 (m, 2 H) 4.78 (dd, J = 7.71, 4.67 Hz, 1 H) 3.52 (t, J =5.81 Hz, 2 H) 2.05-2.17 (m, 1H) 1.78-1.89 (m, 1 H) 1.59- 1.76 (m, 2 H) L75

5-(2-benzylpyrrolidin- 1-yl)sulfonylquinolin- 8-ol MS (ES+) m/z 369.0[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (br. s., 1 H) 9.09 (dd, J= 8.84, 1.52 Hz, 1 H) 8.98 (dd, J = 4.29, 1.52 Hz, 1 H) 8.18 (d, J =8.34 Hz, 1 H) 7.79 (dd, J = 8.84, 4.04 Hz, 1 H) 7.10-7.31 (m, 6H) 3.86(t, J = 8.46 Hz, 1 H) 3.15-3.30 (m, 3 H) 2.84- 2.95 (m, 1 H) 2.62 (dd, J= 13.14, 9.60 Hz, 1 H) 1.63-1.76 (m, 1 H) 1.36- 1.60 (m, 3 H) L 76

5-(2- cyclohexylpyrrolidin- 1-yl)sulfonylquinolin- 8-ol MS (ES+) m/z361.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (br. s., 1 H) 9.04(dd, J = 8.84, 1.52 Hz, 1 H) 8.98 (dd, J = 4.04, 1.52 Hz, 1 H) 8.13 (d,J = 8.34 Hz, 1 H) 7.78 (dd, J = 8.84, 4.04 Hz, 1 H) 7.20 (d, J = 8.34Hz, 1 H) 3.58-3.65 (m, 1 H) 3.05-3.13 (m, 2 H) 1.35- 1.68 (m, 10 H)0.98-1.14 (m, 2 H) 0.83 (d, J = 7.83 Hz, 3 H) L 77

5-[2-(4- methoxyphenyl)pyrrolidin- 1- yl]sulfonylquinolin-8- ol MS (ES+)m/z 385.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (br. s., 1 H)8.93 (dd, J = 4.29, 1.52 Hz, 1 H) 8.83 (dd, J = 8.84, 1.52 Hz, 1 H) 7.98(d, J = 8.34 Hz, 1 H) 7.67 (dd, J = 8.72, 4.17 Hz, 1 H) 7.06 (d, J =8.34 Hz, 1 H) 6.98 (d, J = 8.84 Hz, 2 H) 6.63 (d, J = 8.59 Hz, 2 H) 4.72(dd, J = 7.71, 4.93 Hz, 1 H) 3.67 (s, 3 H) 3.49 (t, J = 6.44 Hz, 2 H)2.02-2.14 (m, 1 H) 1.77-1.89 (m, 1 H) 1.67 (td, J = 11.75, 5.56 Hz, 2H)L 78

5-(2- isopropylpyrrolidin-1- yl)sulfonylquinolin-8- ol MS (ES+) m/z321.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (br. s., 1 H) 9.06(dd, J = 8.72, 1.39 Hz, 1 H) 8.98 (dd, J = 4.04, 1.52 Hz, 1 H) 8.13 (d,J = 8.59 Hz, 1 H) 7.79 (dd, J = 8.84, 4.04 Hz, 1 H) 7.20 (d, J = 8.34Hz, 1 H) 3.60 (dt, J = 8.21, 4.86 Hz, 1 H) 3.30-3.40 (m, 1 H) 3.08-3.17(m, 1 H) 1.87-2.00 (m, 1 H) 1.55-1.70 (m, 2 H) 1.43-1.55 (m, 1 H)1.30-1.41 (m, 1 H) 0.78 (d, J = 6.82 Hz, 3 H) 0.73 (d, J = 6.82 Hz, 3 H)L 79

5-[2-(4- pyridyl)pyrrolidin-1- yl]sulfonylquinolin-8- ol MS (ES+) m/z356.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (br. s., 1 H) 8.96(dd, J = 4.04, 1.52 Hz, 1 H) 8.90 (dd, J = 8.84, 1.52 Hz, 1 H) 8.29-8.34(m, 2 H) 8.06 (d, J = 8.34 Hz, 1 H) 7.73 (dd, J = 8.72, 4.17 Hz, 1 H)7.13-7.16 (m, 2 H) 7.10 (d, J = 8.34 Hz, 1 H) 4.80 (dd, J = 8.46, 4.17Hz, 1 H) 3.52-3.59 (m, 1 H) 3.46 (dt, J = 9.92, 6.79 Hz, 1 H) 2.08- 2.19(m, 1 H) 1.76-1.86 (m, 1 H) 1.61-1.73 (m, 2 H) L 80

5-[2-(2- pyridyl)pyrrolidin-1- yl]sulfonylquinolin-8- ol MS (ES+) m/z356.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (br. s., 1 H) 8.94(dd, J = 4.04, 1.52 Hz, 1 H) 8.89 (dd, J = 8.84, 1.52 Hz, 1 H) 8.32-8.35(m, 1 H) 8.05 (d, J = 8.34 Hz, 1 H) 7.69 (dd, J = 8.72, 4.17 Hz, 1 H)7.56 (td, J = 7.71, 1.77 Hz, 1 H) 7.21 (d, J = 7.83 Hz, 1 H) 7.09-7.15(m, 2 H) 4.83 (dd, J = 8.08, 3.79 Hz, 1 H) 3.43-3.57 (m, 2 H) 2.07 (dt,J = 11.49, 8.02 Hz, 1 H) 1.80- 1.94 (m, 2 H) 1.65-1.76(m, 1H) L 81

5-[2-[2- (trifluoromethyl)phenyl] pyrrolidin-1- yl]sulfonylquinolin-8-ol MS (ES+) m/z 423.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.00(br. s., 1 H) 8.95 (dd, J = 4.04, 1.52 Hz, 1 H) 8.91 (dd, J = 8.84, 1.52Hz, 1 H) 7.97 (d, J = 8.34 Hz, 1 H) 7.72 (dd, J = 8.84, 4.04 Hz, 1 H)7.54 (d, J = 6.57 Hz, 1 H) 7.19-7.33 (m, 3 H) 7.03 (d, J = 8.34 Hz, 1 H)5.05 (dd, J = 8.46, 4.42 Hz, 1 H) 3.67-3.74 (m, 1 H) 3.54-3.62 (m, 1 H)2.16- 2.27 (m, 1 H) 1.86-1.95 (m, 1 H) 1.72- 1.81 (m, 1 H) 1.58 (dd, J =11.75, 5.94 Hz, 1 H) L 82

5-(2- isobutylpyrrolidin-1- yl)sulfonylquinolin-8- ol MS (ES+) m/z 335.2[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (br. s., 1 H) 9.07 (dd, J= 8.84, 1.52 Hz, 1 H) 8.98 (dd, J = 4.04, 1.52 Hz, 1 H) 8.11 (d, J =8.34 Hz, 1 H) 7.78 (dd, J = 8.84, 4.29 Hz, 1 H) 7.21 (d, J = 8.34 Hz, 1H) 3.64-3.73 (m, 1 H) 3.24 (td, J = 6.57, 2.78 Hz, 2 H) 1.67-1.79 (m, 1H) 1.33-1.63 (m, 5 H) 1.19-1.28 (m, 1 H) 0.79 (dd, J = 8.97, 6.44 Hz, 6H) L 83

5-[(4-hydroxy-4- phenyl-1- piperidyl)sulfonyl] quinolin-8-ol MS (ES+)m/z 385.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.09 (br. s., 1 H)9.11 (dd, J = 8.84, 1.52 Hz, 1 H) 9.00 (dd, J = 4.17, 1.39 Hz, 1 H) 8.13(d, J = 8.34 Hz, 1 H) 7.79 (dd, J = 8.84, 4.04 Hz, 1 H) 7.34-7.40 (m, 2H) 7.17-7.32 (m, 4 H) 4.94 (s, 1 H) 3.62 (d, J = 11.12 Hz, 2 H)2.68-2.78 (m, 2 H) 1.90 (td, J = 12.82, 4.17 Hz, 2 H) 1.61 (d, J = 12.38Hz, 2 H) L 84

5-[(4-benzyl-1- piperidyl)sulfonyl] quinolin-8-ol MS (ES+) m/z 383.2[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.03 (br. s., 1 H) 8.94-8.99(m, 2 H) 8.05 (d, J = 8.34 Hz, 1 H) 7.72- 7.77 (m, 1 H) 7.11-7.26 (m, 4H) 7.06- 7.10 (m, 2 H) 3.65 (d, J = 11.87 Hz, 2 H) 2.42 (d, J = 6.82 Hz,2 H) 2.29-2.38 (m, 2 H) 1.43-1.61 (m, 3 H) 1.03- 1.17 (m, 2 H) L 85

[1-[(8-hydroxy-5- quinolyl)sulfonyl]-4- piperidyl]-phenyl- methanone MS(ES+) m/z 397.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.07 (br. s, 1H) 9.04 (dd, J = 8.84, 1.52 Hz, 1 H) 9.00 (dd, J = 4.17, 1.39 Hz, 1 H)8.10 (d, J = 8.34 Hz, 1 H) 7.89-7.94 (m, 2 H) 7.79 (dd, J = 8.72, 4.17Hz, 1 H) 7.57-7.64 (m, 1 H) 7.44-7.51 (m, 2 H) 7.23 (d, J = 8.34 Hz, 1H) 3.72 (d, J = 12.13 Hz, 2 H) 3.41-3.51 (m, 1 H) 2.54-2.63 (m, 2 H)1.81 (d, J = 11.12 Hz, 2 H) 1.42- 1.56 (m, 2 H) L 86

1-[1-[(8-hydroxy-5- quinolyl)sulfonyl]-4- phenyl-4- piperidyl]ethanoneMS (ES+) m/z 411.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.09 (br.s., 1 H) 8.92-8.99 (m, 2 H) 8.07 (d, J = 8.34 Hz, 1 H) 7.76 (dd, J =8.84, 4.29 Hz, 1 H) 7.31-7.38 (m, 2 H) 7.23-7.29 (m, 3 H) 7.19 (d, J =8.34 Hz, 1 H) 3.33-3.40 (m, 2 H) 2.72- 2.81 (m, 2 H) 2.40 (d, J = 13.90Hz, 2 H) 1.90-2.00 (m, 2 H) 1.78 (s, 3 H) L 87

8-[(8-hydroxy-5- quinolyl)sulfonyl]-1- phenyl-1,3,8-triazaspiro[4.5]decan- 4-one MS (ES+) m/z 439.0 [M + H]⁺ ¹H NMR (400MHz, DMSO-d6) δ ppm 11.17 (br. s., 1 H) 8.99-9.07 (m, 2 H) 8.77 (s, 1 H)8.16 (d, J = 8.59 Hz, 1 H) 7.83 (dd, J = 8.84, 4.29 Hz, 1 H) 7.22 (d, J= 8.34 Hz, 1 H) 7.11 (t, J = 8.08 Hz, 2 H) 6.69-6.75 (m, 1 H) 6.57 (d, J= 7.83 Hz, 2 H) 4.54 (s, 2 H) 3.68-3.77 (m, 2 H) 3.27-3.36 (m, 2 H)2.35-2.47 (m, 2 H) 1.63 (d, J = 13.64 Hz, 2 H) L 88

methyl 4-[(8-hydroxy- 5- quinolyl)sulfonyl] piperazine-1-carboxylate MS(ES+) m/z 352.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.13 (br. s.,1 H) 8.94-9.02 (m, 2 H) 8.08 (d, J = 8.34 Hz, 1 H) 7.77 (dd, J = 8.72,4.17 Hz, 1 H) 7.21 (d, J = 8.34 Hz, 1 H) 3.52 (s, 3 H) 3.36-3.41 (m, 4H) 2.96-3.05 (m, 4 H) L 89

5-[4-(3- methoxypropyl)piperazin- 1- yl]sulfonylquinolin-8- ol MS (ES+)m/z 366.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.11 (br. s, 1 H)8.97-9.03 (m, 2 H) 8.08 (d, J = 8.34 Hz, 1 H) 7.74- 7.80 (m, 1 H) 7.22(d, J = 8.59 Hz, 1 H) 3.23 (t, J = 6.32 Hz, 2 H) 3.14 (s, 3 H) 2.97 (br.s., 4 H) 2.34 (br. s., 4 H) 2.25 (br. s., 2 H) 1.49-1.59 (m, 2 H) L 90

2-[4-[(8-hydroxy-5- quinolyl)sulfonyl] piperazin-1-yl]benzonitrile MS(ES+) m/z 395.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.19 (br. s.,1 H) 9.04 (dd, J = 8.84, 1.52 Hz, 1 H) 8.99-9.02 (m, 1 H) 8.15 (d, J =8.59 Hz, 1 H) 7.80 (dd, J = 8.84, 4.29 Hz, 1 H) 7.68 (dd, J = 7.83, 1.52Hz, 1 H) 7.59 (td, J = 7.96, 1.52 Hz, 1 H) 7.25 (d, J = 8.34 Hz, 1 H)7.09-7.17 (m, 2H) 3.17 (d, J = 5.05 Hz, 8 H) L 91

5-(3- azabicyclo[3.2.2]nonan- 3- ylsulfonyl)quinolin-8- ol MS (ES+) m/z333.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.02 (br. s, 1 H)8.94-9.00 (m, 2 H) 8.06 (d, J = 8.34 Hz, 1 H) 7.78 (dd, J = 8.72, 4.17Hz, 1 H) 7.18 (d, J = 8.34 Hz, 1 H) 3.27 (d, J = 4.04 Hz, 4 H) 2.01 (br.s., 2 H) 1.46-1.59 (m, 8 H) L 92

5-[4-(2- phenylphenyl)piperazin- 1- yl]sulfonylquinolin-8- ol MS (ES+)m/z 446.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.14 (br. s., 1 H)9.01 (dd, J = 4.04, 1.52 Hz, 1 H) 8.92 (dd, J = 8.84, 1.52 Hz, 1 H) 8.07(d, J = 8.59 Hz, 1 H) 7.75 (dd, J = 8.72, 4.17 Hz, 1 H) 7.42-7.46 (m, 2H) 7.18-7.29 (m, 5 H) 7.16 (dd, J = 7.45, 1.64 Hz, 1H) 7.04-7.10 (m, 1H) 7.01 (d, J = 8.08 Hz, 1 H) 2.89 (br. s., 4 H) 2.74 (d, J = 4.29 Hz, 4H) L 93

5-[4-(2,5- dimethylphenyl)piperazin- 1- yl]sulfonylquinolin-8- ol MS(ES+) m/z 398.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.15 (br. s, 1H) 8.99-9.06 (m, 2 H) 8.13 (d, J = 8.34 Hz, 1 H) 7.80 (dd, J = 8.84,4.04 Hz, 1 H) 7.24 (d, J = 8.34 Hz, 1 H) 6.98 (d, J = 7.58 Hz, 1 H)6.73- 6.79 (m, 2 H) 3.14 (br. s., 4 H) 2.83 (t, J = 4.55 Hz, 4 H) 2.21(s, 3 H) 2.04 (s, 3 H) L 94

5-[4-[4- (trifluoromethyl)phenyl] piperazin-1- yl]sulfonylquinolin-8- olMS (ES+) m/z 438.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm11.13 (br. s,1 H) 9.03 (dd, J = 8.84, 1.52 Hz, 1 H) 8.99 (dd, J = 4.17, 1.39 Hz, 1 H)8.13 (d, J = 8.34 Hz, 1 H) 7.79 (dd, J = 8.72, 4.17 Hz, 1 H) 7.47 (d, J= 9.09 Hz, 2 H) 7.23 (d, J = 8.34 Hz, 1 H) 7.00 (d, J = 8.84 Hz, 2 H)3.29-3.32 (m, 4 H) 3.10-3.15 (m, 4H) L 95

5-[4-[bis(4- fluorophenyl)methyl] piperazin-1- yl]sulfonylquinolin-8- olMS (ES+) m/z 496.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (br.s, 1 H) 8.98-9.02 (m, 2 H) 8.06 (d, J = 8.59 Hz, 1 H) 7.73- 7.77 (m, 1H) 7.34 (dd, J = 8.21, 5.68 Hz, 4 H) 7.23 (d, J = 8.34 Hz, 1 H) 7.02-7.10 (m, 4 H) 4.36 (s, 1 H) 3.00 (br. s., 4 H) 2.29 (br. s., 4 H) L 96

5-[4-(4- fluorophenyl)piperazin- 1-yl]sulfonylquinolin- 8-ol MS (ES+)m/z 388.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (br. s., 1 H)9.03 (dd, J = 8.84, 1.52 Hz, 1 H) 8.99 (dd, J = 4.04, 1.52 Hz, 1 H) 8.13(d, J = 8.34 Hz, 1 H) 7.79 (dd, J = 8.84, 4.29 Hz, 1 H) 7.24 (d, J =8.59 Hz, 1 H) 6.99-7.05 (m, 2 H) 6.87-6.92 (m, 2 H) 3.10 (dd, J = 16.67,5.56 Hz, 8 H) L 97

5-[4-(2,3- dichlorophenyl)piperazin- 1- yl]sulfonylquinolin-8- ol MS(ES+) m/z 438.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.17 (br. s, 1H) 9.05 (dd, J = 8.84, 1.52 Hz, 1 H) 9.01 (dd, J = 4.17, 1.39 Hz, 1 H)8.14 (d, J = 8.59 Hz, 1 H) 7.80 (dd, J = 8.84, 4.29 Hz, 1 H) 7.27-7.33(m, 2 H) 7.25 (d, J = 8.34 Hz, 1 H) 7.12 (dd, J = 6.95, 2.65 Hz, 1 H)3.17 (br. s., 4H) 3.01 (d, J = 4.29 Hz, 4 H) L 98

5-[4-(1,2- benzothiazol-3- yl)piperazin-1- yl]sulfonylquinolin-8- ol MS(ES+) m/z 427.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.15 (br. s.,1 H) 9.06 (d, J = 8.84 Hz, 1 H) 9.01 (d, J = 4.04 Hz, 1 H) 8.14 (d, J =8.34 Hz, 1 H) 8.03 (d, J = 8.08 Hz, 1 H) 7.99 (d, J = 8.34 Hz, 1 H) 7.80(dd, J = 8.72, 4.17 Hz, 1 H) 7.53 (t, J = 7.33 Hz, 1 H) 7.35-7.41 (m, 1H) 7.25 (d, J = 8.34 Hz, 1 H) 3.45 (br. s., 4 H) 3.25 (br. s., 4 H) L 99

5-[3-[4- (trifluoromethoxy) phenoxy]azetidin-1- yl]sulfonylquinolin-8-ol MS (ES+) m/z 441.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.23(br. s, 1 H) 9.00 (dd, J = 4.04, 1.52 Hz, 1 H) 8.96 (dd, J = 8.84, 1.52Hz, 1 H) 8.15 (d, J = 8.34 Hz, 1 H) 7.80 (dd, J = 8.72, 4.17 Hz, 1 H)7.24 (t, J = 8.97 Hz, 3 H) 6.84-6.89 (m, 2 H) 4.91-4.99 (m, 1 H) 4.21(dd, J = 9.35, 6.32 Hz, 2 H) 3.73 (dd, J = 9.47, 4.67 Hz, 2 H) L 100

5-[4-(2,3- dimethylphenyl)piperazin- 1- yl]sulfonylquinolin-8- ol MS(ES+) m/z 398.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.13 (br. s, 1H) 9.04 (dd, J = 8.84, 1.52 Hz, 1 H) 9.01 (dd, J = 4.04, 1.52 Hz, 1 H)8.13 (d, J = 8.34 Hz, 1 H) 7.80 (dd, J = 8.72, 4.17 Hz, 1 H) 7.25 (d, J= 8.34 Hz, 1 H) 6.98-7.03 (m, 1 H) 6.85 (dd, J = 10.86, 7.83 Hz, 2 H)3.16 (br. s., 4 H) 2.80 (br. s., 4 H) 2.15 (s, 3 H) 2.01 (s, 3 H) L 101

5-[4-[(4- fluorophenyl)methyl] piperazin-1- yl]sulfonylquinolin-8- ol MS(ES+) m/z 402.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (br. s, 1H) 8.98 (dq, J = 6.44, 1.39 Hz, 2 H) 8.07 (d, J = 8.34 Hz, 1 H)7.73-7.78 (m, 1 H) 7.19- 7.26 (m, 3 H) 7.04-7.11 (m, 2 H) 3.40 (s, 2 H)2.99 (br. s., 4 H) 2.35 (br. s., 4 H) L 102

5-[(3-phenyl-1- piperidyl)sulfonyl] quinolin-8-ol MS (ES+) m/z 369.2[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (br. s, 1 H) 9.01 (dd, J= 8.72, 1.64 Hz, 1 H) 8.98 (dd, J = 4.04, 1.52 Hz, 1 H) 8.09 (d, J =8.34 Hz, 1 H) 7.77 (dd, J = 8.84, 4.29 Hz, 1 H) 7.25-7.30 (m, 2 H)7.18-7.23 (m, 4 H) 3.73 (d, J = 10.86 Hz, 1 H) 3.66 (d, J = 11.37 Hz, 1H) 2.68 (d, J = 10.36 Hz, 1 H) 2.46-2.58 (m, 2 H) 1.75 (d, J = 9.35 Hz,2 H) 1.47-1.55 (m, 2 H) L 103

tert-butyl 4-[(8- hydroxy-5- quinolyl)sulfonyl] piperazine-1-carboxylateMS (ES+) m/z 394.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.09 (br.s, 1 H) 9.00 (s, 1 H) 8.97-8.99 (m, 1 H) 8.08 (d, J = 8.34 Hz, 1 H)7.75-7.79 (m, 1 H) 7.21 (d, J = 8.34 Hz, 1 H) 3.34 (d, J = 4.29 Hz, 4 H)2.94-2.99 (m, 4 H) 1.32 (s, 9 H) L 104

5-piperazin-1- ylsulfonylquinolin-8- ol MS (ES+) m/z 294.0 [M + H]⁺ ¹HNMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 2 H) 9.02-9.09 (m, 2 H) 8.16(d, J = 8.34 Hz, 1 H) 7.86 (dd, J = 8.72, 4.42 Hz, 1 H) 7.32 (d, J =8.34 Hz, 1 H) 3.24 (d, J = 5.05 Hz, 4 H) 3.10 (br. s., 4 H) L 105

tert-butyl 4-[(8- hydroxy-5- quinolyl)sulfonyl]-3- methyl-piperazine-1-carboxylate MS (ES+) m/z 408.2 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm11.08 (br. s., 1 H) 8.99 (dd, J = 4.04, 1.52 Hz, 1 H) 8.78 (dd, J =8.84, 1.26 Hz, 1 H) 8.14 (d, J = 8.34 Hz, 1 H) 7.79 (dd, J = 8.84, 4.04Hz, 1 H) 7.18 (d, J = 8.34 Hz, 1 H) 4.07 (br. s., 1 H) 3.85 (br. s., 1H) 3.70 (d, J = 13.90 Hz, 1 H) 3.40-3.46 (m, 2 H) 3.00-3.11 (m, 1 H)2.70-2.91 (m, 1 H) 1.35 (s, 9 H) 0.98 (d, J = 5.56 Hz, 3 H) L 106

5-(2-methylpiperazin- 1-yl)sulfonylquinolin- 8-ol MS (ES+) m/z 308.0[M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm9.60 (br. s., 1 H) 9.01-9.14 (m,2 H) 8.82 (d, J = 8.84 Hz, 1 H) 8.19 (d, J = 8.34 Hz, 1 H) 7.85 (dd, J =8.59, 4.29 Hz, 1 H) 7.25 (d, J = 8.34 Hz, 1 H) 4.27 (br. s., 1 H)3.55-3.63 (m, 1 H) 3.29 (t, J = 12.00 Hz, 1 H) 3.08-3.21 (m, 2 H) 2.90(d, J = 12.38 Hz, 1 H) 2.60 (d, J = 12.63 Hz, 1H) 1.24 (d, J = 7.07 Hz,3H) L

Example 107: 7-iodo-5-(p-tolylsulfonyl)quinolin-8-ol—Method N

Step 1: 5-iodo-8-((4-methoxybenzyl)oxy)quinolone

The compound was prepared as previously described in WO198901465 andSynthesis 2006, 8, 1325-1332.

Step 2: 8-((4-methoxybenzyl)oxy)-5-tosylquinoline

A mixture of 5-iodo-8-((4-methoxybenzyl)oxy)quinoline (740 mg, 1.892mmol), copper(I) iodide (36.0 mg, 0.189 mmol), sodium(S)-pyrrolidine-2-carboxylate (51.9 mg, 0.378 mmol) and sodium4-methylbenzenesulfinate (404 mg, 2.27 mmol) in DMSO (10 ml) was heatedto 90° C. overnight. The DMSO mixture was concentrated further under anitrogen stream with heating at 50° C. to approximately 15 ml of volume.All materials were poured onto a silica pad atop a Thomson (90 g)column. The material was purified by automated normal-phasechromatography using 0-80% ethyl acetate/hexanes as an eluent. Two peakswere collected one as the title compound (200.9 mg, 25% yield) andrecovered starting material (5-iodo-8-((4-methoxybenzyl)oxy)quinolone,465 mg). MS (ES+) m/z 420.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.32(s, 3H) 3.77 (s, 3H) 5.33 (s, 2H) 7.00 (d, J=8.59 Hz, 2H) 7.38 (d,J=8.34 Hz, 2H) 7.48 (d, J=8.59 Hz, 2H) 7.54 (d, J=8.59 Hz, 1H) 7.69 (dd,J=8.72, 4.17 Hz, 1H) 7.84 (d, J=8.34 Hz, 2H) 8.47 (d, J=8.34 Hz, 1H)8.86 (dd, J=8.72, 1.39 Hz, 1H) 8.91 (dd, J=4.04, 1.26 Hz, 1H).

Step 3: 5-(p-tolylsulfonyl)quinolin-8-ol

To a slurry of 8-((4-methoxybenzyl)oxy)-5-tosylquinoline (500 mg, 1.192mmol) in dichloromethane was added trifluoroacetic acid (0.092 ml, 1.192mmol). The reaction was maintained at ambient temperature for 1 hourprior to concentration to an oily residue. Water was added and a gooeysolid formed. The aqueous solution was neutralized with 6 M sodiumhydroxide and diluted with dichloromethane. The layers were separatedand organic dried over sodium sulfate. Concentration gave a sticky solidthat was purified by automated normal-phase chromatography using 0-10%methanol/dichloromethane as an eluent. (420 mg, 85% yield). MS (ES+) m/z301.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 3.34 (br. s.,1H) 7.27 (d, J=8.34 Hz, 1H) 7.37 (d, J=8.34 Hz, 2H) 7.72 (dd, J=8.72,4.17 Hz, 1H) 7.83 (d, J=8.34 Hz, 2H) 8.39 (d, J=8.34 Hz, 1H) 8.88 (dd,J=8.84, 1.52 Hz, 1H) 8.94 (dd, J=4.04, 1.52 Hz, 1H).

Step 4: 7-iodo-5-(p-tolylsulfonyl)quinolin-8-ol

A solution of 5-(p-tolylsulfonyl)quinolin-8-ol (50 mg, 0.17 mmol) andN-iodosuccinimide (37.57 mg, 0.17 mmol) in chloroform was vigorouslystirred at 40° C. After 1 hour, the resulting solution was filtered andthe organic phase was washed with 10% aqueous sodium thiosulfatesolution (1×2 ml) and layers separated. The solvent was removed bynitrogen stream and product suspended in ethyl acetate and diluted withdiethyl ether to yield yellow solids. The solids were collected byfiltration and dried. The solids were placed in a vacuum oven forseveral hours to remove trace solvent. (33.6 mg, 47% yield). MS (ES+)m/z 448.9 [M+Na]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3H) 7.39 (d,J=8.08 Hz, 2H) 7.77 (dd, J=8.21, 4.17 Hz, 1H) 7.89 (d, J=8.08 Hz, 2H)8.64 (s, 1H) 8.86 (d, J=8.84 Hz, 1H) 8.95 (d, J=4.29 Hz, 1H).

The following analogs were synthesized using the Method N as describedabove.

Preparation Example Name R⁶ Data Information 108 7-bromo-5-(p- Br MS(ES+) m/z 379.1 [M + H]⁺ Using N- tolylsulfonyl)quinolin- ¹H NMR (400MHz, DMSO-d6) δ bromosuccimide 8-ol ppm 2.33 (s, 3 H) 7.39 (d, J = 8.59Hz, 2 H) 7.77 (dd, J = 8.59, 4.29 Hz, 1 H) 7.91 (d, J = 8.34 Hz, 2H)8.51 (s, 1 H) 8.88 (d, J = 7.83 Hz, 1 H) 8.96 (d, J = 4.04 Hz, 1 H) 1097-chloro-5-(p- Cl MS (ES+) m/z 334.0 [M + H]⁺ Using N-tolylsulfonyl)quinolin- ¹H NMR (400 MHz, DMSO-d6) δ chlorosuccimide 8-olppm 2.33 (s, 3 H) 7.39 (d, J = 8.59 Hz, 2 H) 7.77 (dd, J = 8.72, 4.17Hz, 1 H) 7.92 (d, J = 8.08 Hz, 2 H) 8.42 (s, 1 H) 8.89 (dd, J = 8.72,1.39 Hz, 1 H) 8.99 (dd, J = 4.17, 1.39 Hz, 1H)

Example 110: 7-fluoro-5-(p-tolylsulfonyl)quinolin-8-ol

Step 1: 7-fluoroquinolin-8-ol

To a solution of 2-amino-6-fluoro-phenol (2000 mg, 15.73 mmol) andnitrobenene (10 ml) in a sealable reaction pressure vessel was added inportions sulfuric acid (2 mL, 37.52 mmol). Glycerol (4.8 mL, 65.15 mmol)was added in one portion, and the solution turned to dark brown. Thevessel was flushed with nitrogen, sealed and heated to 140° C. for 6hours. The reaction mixture was cooled to ambient, diluted with (30 mL)ice/water mixture, extracted (2×200 mL) methyl tert-butyl ether. Theaqueous phase was neutralized to pH ˜6-7 by slow addition of 6N sodiumhydroxide. The resulting black precipitate was collected by filtrationand the water solution was extracted with ethyl acetate 3 times. Theorganic extracts were combined with the black precipitate, concentratedin vacuo, and purified by automated normal-phase chromatography using0-10% methanol/dichloromethane as an eluent. The title compound wasisolated as a solid (1.56 g, 59% yield). MS (ES+) m/z 164.9 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) δ ppm 7.43-7.49 (m, 1H) 7.50-7.57 (m, 2H) 8.37(dd, J=8.21, 1.64 Hz, 1H) 8.90 (dd, J=4.17, 1.64 Hz, 1H) 10.26 (br. s.,1H).

Step 2: 7-fluoro-5-iodo-quinolin-8-ol

A solution of 7-fluoroquinolin-8-ol (250 mg, 1.53 mmol) andN-iodosuccinimide (413.69 mg, 1.84 mmol) in chloroform was vigorouslystirred at 40° C. After 15 minutes the reaction was diluted withdichloromethane, extracted (2×20 mL) 10% sodium thiosulfate solution anddried over sodium sulfate. The pale yellow solids were taken on insubsequent reactions without additional purification. (429.6 mg, 97%yield). MS (ES+) m/z 290.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.67(dd, J=8.59, 4.29 Hz, 1H) 8.17 (d, J=10.61 Hz, 1H) 8.25-8.35 (m, 1H)8.90 (dd, J=4.04, 1.52 Hz, 1H) 10.62 (br. s., 1H).

Step 3: 7-fluoro-5-iodo-8-benzyloxyqunioline

To a solution of 7-fluoro-5-iodo-quinolin-8-ol (425 mg, 1.47 mmol) in (5mL) DMF was added sodium hydride, 60% suspension in mineral oil (70.58mg, 1.76 mmol). After 5 minutes benzyl bromide (0.21 mL, 1.76 mmol) wasadded slowly dropwise. The reaction was maintained at ambienttemperature. The reaction was quenched by addition of water. Ethylacetate was added and the layers separated. The aqueous layer wasextracted (2×20 mL) ethyl acetate. The organics were combined and driedover sodium sulfate. Concentration gave an oily residue that waspurified by automated normal-phase chromatography using 0-100% ethylacetate/hexanes as an eluent. (446.9 mg, 80% yield). MS (ES+) m/z 401.9[M+2H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 5.47 (s, 2H) 7.28-7.41 (m, 3H)7.44-7.52 (m, 2H) 7.69 (dd, J=8.59, 4.29 Hz, 1H) 8.25 (d, J=10.11 Hz,1H) 8.36 (dd, J=8.72, 1.39 Hz, 1H) 9.00 (dd, J=4.04, 1.52 Hz, 1H).

Step 4: 8-benzyloxy-7-fluoro-5-(p-tolylsulfanyl)quinolone

4-mercaptotoluene (163.12 mg, 1.31 mmol), potassium carbonate (121.02mg, 0.88 mmol) and 7-fluoro-5-iodo-8-benzyloxyqunioline (166 mg, 0.44mmol) were charged in a microwave vial. The vial was placed undernitrogen and copper (I) iodide (4.17 mg, 0.02 mmol), ethylene glycol(0.02 mL, 0.44 mmol) and isopropyl alcohol (2 mL) were added at ambienttemperature. The vial was submitted to microwave irradiation on highabsorption at 100° C. for 30 minutes. The mixture was cooled to ambienttemperature and filtered through a cake of Celite washing with ethylacetate. Purification was accomplished by automated normal-phasechromatography using 0-30% ethyl acetate/hexanes as an eluent to affordthe title compound (85.9 mg, 52% yield). MS (ES+) m/z 376.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) δ ppm 2.27 (s, 3H) 5.49 (s, 2H) 7.13-7.23 (m, 4H)7.30-7.43 (m, 3H) 7.45-7.54 (m, 2H) 7.58 (d, J=10.61 Hz, 1H) 7.63 (dd,J=8.59, 4.04 Hz, 1H) 8.62 (dd, J=8.59, 1.77 Hz, 1H) 9.04 (dd, J=4.04,1.52 Hz, 1H).

Step 5: 8-benzyloxy-7-fluoro-5-(p-tolylsulfonyl)quinolone

To a stirred solution of8-benzyloxy-7-fluoro-5-(p-tolylsulfanyl)quinoline (100 mg, 0.27 mmol) in(2 mL) dry acetonitrile was added N-methylmorpholine N-oxide (93.61 mg,0.80 mmol) at ambient temperature. After 5 minutes tetrapropylammoniumperruthenate (4.68 mg, 0.01 mmol) was added to the mixture and warmed to40° C. Additional tetrapropylammoniumperruthenate (1 equivalent) andN-methylmorpholine N-oxide (1 equivalent) were added after one hour andthe reaction mixture was resubjected to the reaction conditionsovernight. The mixture was cooled to ambient temperature andconcentrated to a residue. The material was suspended in ethyl acetateand filtered through a cake of silica gel. The filtrate was concentratedand purified by automated normal-phase chromatography using 0-30% ethylacetate/hexanes as an eluent to afford the title compound (60.2 mg, 55%yield). MS (ES+) m/z 408.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.34(s, 3H) 5.61 (s, 2H) 7.30-7.44 (m, 5H) 7.47-7.54 (m, 2H) 7.71 (dd,J=8.72, 4.17 Hz, 1H) 7.90-7.98 (m, 2H) 8.46 (d, J=10.61 Hz, 1H)8.90-8.97 (m, 1H) 9.06 (dd, J=4.04, 1.52 Hz, 1H).

Step 6: 7-fluoro-5-(p-tolylsulfonyl)quinolin-8-ol

A mixture of 8-benzyloxy-7-fluoro-5-(p-tolylsulfonyl)quinoline (70 mg,0.17 mmol) dissolved in acetic acid (0.50 mL) was added hydrobromic acid(0.50 mL). The resultant mixture was heated to 100° C. for 3 hours. Thematerial was cooled to ambient temperature and neutralized with 6 Msodium hydroxide. The aqueous solution was extracted (3×2 mL)dichloromethane, organics combined, filtered through a phase separatortube and concentrated to a residue. Purification was accomplished byautomated normal-phase chromatography using with 0-10%methanol/dichloromethane as an eluent. The impure material was dissolvedin a minimum amount of dichloromethane and purified by reversed phaseHPLC-Gilson eluting 5-95% acetonitrile/water, 0.05% trifluoroaceticacid. An orange solid (38.3 mg, 70% yield) was obtained. MS (ES+) m/z318.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3H) 3.42 (br. s,1H) 7.39 (d, J=8.34 Hz, 2H) 7.71 (dd, J=8.72, 4.17 Hz, 1H) 7.91 (d,J=7.83 Hz, 2H) 8.42 (d, J=11.12 Hz, 1H) 8.90 (dt, J=8.34, 1.01 Hz, 1H)8.97 (d, J=4.04 Hz, 1H).

Example 111: 7-methyl-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol

Step 1: 8-fluoro-7-methyl-quinoline

8-fluoro-7-methyl-quinoline was prepared in a similar manner as Example110, step 1. The product was prepared from 2-fluoro-3-methyl-aniline(15.98 mmol) providing 2.29 g (89% yield). ¹H NMR (400 MHz, DMSO-d6) δppm 2.46 (d, J=2.53 Hz, 3H) 7.51 (dd, J=8.08, 7.07 Hz, 1H) 7.57 (dd,J=8.34, 4.04 Hz, 1H) 7.73 (d, J=8.34 Hz, 1H) 8.39 (dt, J=8.34, 1.77 Hz,1H) 8.92 (dd, J=4.17, 1.64 Hz, 1H).

Step 2: 8-fluoro-7-methyl-quinoline-5-sulfonyl chloride

8-fluoro-7-methyl-quinoline-5-sulfonyl chloride was prepared in asimilar manner as in Method K, Step 1. The product was prepared from8-fluoro-7-methyl-quinoline (3.1 mmol) providing 509.2 mg (63% yield) ofthe title compound. MS (ES+) m/z 260.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6)δ ppm 2.51-2.52 (m, 3H) 7.90 (dd, J=8.72, 4.67 Hz, 1H) 8.01 (d, J=7.33Hz, 1H) 9.09 (dd, J=4.80, 1.52 Hz, 1H) 9.48 (dt, J=8.72, 1.71 Hz, 1H).

Step 3: 8-tert-butoxy-7-methyl-5-pyrrolidin-1-ylsulfonyl-quinoline

8-tert-butoxy-7-methyl-5-pyrrolidin-1-ylsulfonyl-quinoline was preparedin a similar manner as in Method K, Step 2. The product was preparedfrom 8-fluoro-7-methyl-quinoline-5-sulfonyl chloride (0.20 mmol) to give45.2 mg (63% yield) of the title compound. MS (ES+) m/z 349.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 9H) 1.72 (dt, J=6.51, 3.44 Hz, 4H)3.17-3.27 (m, 4H) 3.34 (s, 3H) 7.61-7.70 (m, 1H) 8.06 (s, 1H) 8.96-9.03(m, 2H).

Step 4: 7-methyl-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol

7-methyl-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol was prepared in asimilar manner as in Method K, Step 3. The product was prepared from8-tert-butoxy-7-methyl-5-pyrrolidin-1-ylsulfonyl-quinoline (0.129 mmol)to provide 35 mg (92% yield) of the title compound. MS (ES+) m/z 293.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.73 (m, 4H) 2.43 (s, 3H)3.11-3.20 (m, 4H) 7.76 (dd, J=8.84, 4.29 Hz, 1H) 8.06 (d, J=0.51 Hz, 1H)8.98 (dd, J=4.29, 1.52 Hz, 1H) 9.08 (dd, J=8.59, 1.52 Hz, 1H).

Example 112:7-chloro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol—MethodO

Step 1: 8-fluoroquinoline-5-sulfonyl chloride

8-Fluoroquinoline (2.5 g, 16.99 mmol) was added dropwise with stirringto chlorosulfonic acid (7.04 mL, 105.95 mmol). The resulting mixture wasstirred at 110° C. for 18 h. The reaction mixture was added dropwise toice-water with stirring. The solid was collected by filtration andair-dried to give the product as a beige solid (903 mg, 21.7% yield). MS(ES+) m/z 246.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm: 7.56 (dd,J=10.86, 8.08 Hz, 3H) 7.74 (dd, J=8.72, 4.17 Hz, 3H) 7.98 (dd, J=8.08,5.31 Hz, 3H) 8.99 (dd, J=4.17, 1.64 Hz, 3H) 9.27 (dt, J=8.72, 1.71 Hz,3H).

Step 2:8-tert-butoxy-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinoline

8-fluoroquinoline-5-sulfonyl chloride (250 mg, 1.02 mmol) was dissolvedin THF (1.5 mL). To this solution was added DIPEA (531.85 uL, 3.05mmol), followed by 1-[(4-fluorophenyl)methyl]piperazine (197.68 mg, 1.02mmol). The resulting mixture was stirred at room temperature for 15 min.Complete conversion to intermediate sulfonamide was indicated by LCMS. Asolution of potassium t-butoxide (3053.5 uL, 3.05 mmol, 1M in THF) wasadded and the resulting mixture stirred at ambient temperature for 1hour. The reaction mixture was treated with about 2 mL saturated NaHCO₃and about 2 mL ethyl acetate, agitated vigorously and the layersseparated. Solvent was removed from the organic fraction in vacuo togive a brown residue. The material was taken on without additionalpurification and or characterization. MS (ES+) m/z 458.0 [M+H]⁺.

Step 3:5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonylquinolin-8-ol

Crude(8-tert-butoxy-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinoline(465.34 mg, 1.02 mmol) dissolved in 2 mL THF was treated with 4M HCl indioxane (0.25 mL, 1.02 mmol) overnight. The suspensions were dilutedwith ether and solids collected by filtration. The material was used insubsequent reactions without additional purification and/orcharacterization. MS (ES+) m/z 402.0 [M+H]⁺.

Step 4:7-chloro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol

A solution of5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonylquinolin-8-ol (150mg, 0.370 mmol) suspended in chloroform (2 mL) was added DIPEA (0.07 mL,0.370 mmol). When the mixture became a solution, N-chlorosuccinimide(49.89 mg, 0.370 mmol) was added at ambient temperature. LC/MS at 1 hourshows only starting material. The reaction was heated to 40° C. and anadditional equivalent of N-chlorosuccinimide was added. The vial wascooled to ambient temperature and filtered. The solids were suspendedbetween water and 10% sodium thiosulfate solution for 1 hour. Thesuspension was filtered and yellow solids obtained. MS (ES+) m/z 436.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (d, J=4.04 Hz, 1H) 8.95(dd, J=8.84, 1.52 Hz, 1H) 8.05 (s, 1H) 7.76 (dd, J=8.84, 4.29 Hz, 1H)7.24 (dd, J=8.72, 5.68 Hz, 2H) 7.08 (t, J=8.84 Hz, 2H) 3.31-3.37 (m, 2H)3.02 (br. s., 4H) 2.36 (br. s., 4H).

Example 113: 7-fluoro-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol—Method P

Step 1: 7-fluoroquinolin-8-ol

To a solution of 2-amino-6-fluoro-phenol (2000 mg, 15.73 mmol) andnitrobenzene (10 mL) in a sealable reaction vessel was added in portionssulfuric acid (2 mL, 37.52 mmol). Glycerol (4.8 mL, 65.15 mmol) wasadded in one portion. The vessel was flushed with nitrogen, sealed andheated to 140° C. for 6 hours. The reaction mixture was cooled toambient temperature, nitrobenzene decanted off, oily brown/black residuediluted with 30 ml ice/water mixture, extracted (2×200 ml) with methylt-butyl ether. The aqueous phase was neutralized to pH=6-7 by slowaddition of 6N NaOH. The resulting black precipitate was collected(pouring over a pad of Celite) and the water solution was extracted withethyl acetate 3 times. The organics were combined and concentrated to aresidue and combined with the black solids collected by filtration. Thematerial was purified by SiO₂ chromatography-Biotage eluting 0-10%methanol/dichloromethane yielding a pale green/white solid (1.39 g, 8.54mmol, 54% yield). MS (ES+) m/z 164.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δppm: 10.24 (br. s., 1H) 8.90 (dd, J=4.17, 1.64 Hz, 1H) 8.37 (dd, J=8.34,1.77 Hz, 1H) 7.50-7.58 (m, 2H) 7.41-7.49 (m, 1H).

Step 2: 7-fluoro-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol

To a suspension of in 7-fluoroquinolin-8-ol (0.12 mL, 0.92 mmol) in 5 mldichloroethane was added chlorosulfonic acid (20 drops) at ambienttemperature. The resultant solution was heated to reflux overnight. Thereaction mixture was cooled to 0° C. and pyrrolidine (1 mL, 12.18 mmol)was added. The reaction mixture was allowed to warm to ambienttemperature and concentrated to a residue. Purification was accomplishedby reversed phase HPLC eluting 10-100% acetonitrile/water with 0.05%trifluoroacetic acid as modifier. The product containing fractions werepooled and concentrated to a tan solid (123.4 mg, 33%) as thetrifluoroacetic acid salt. MS (ES+) m/z 297.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.71 (dt, J=6.51, 3.44 Hz, 4H) 3.17-3.23 (m, 4H) 7.77(dd, J=8.84, 4.04 Hz, 1H) 8.09 (d, J=10.86 Hz, 1H) 9.03 (dd, J=4.17,1.39 Hz, 1H) 9.07 (dd, J=8.84, 1.52 Hz, 1H).

The following compounds were synthesized according to one of theprevious methods.

Prep Ex Structure Name Data info 114

5-[4-[(4- fluorophenyl)methyl] piperazin-1- yl]sulfonyl-7-methyl-quinolin-8-ol MS (ES+) m/z 416.0 [M + H]⁺ ¹H NMR (400 MHz,DMSO-d6) δ ppm: 9.31-9.56 (m, 1 H) 8.86- 9.03 (m, 2 H) 8.05 (s, 1 H)7.73 (dd, J = 8.84, 4.29 Hz, 1 H) 7.44 (d, J = 5.31 Hz, 2 H) 7.28 (t, J= 8.72 Hz, 2 H) 4.28 (br. s., 2 H) 3.70-3.88 (m, 2 H) 3.23-3.40 (m, 2 H)2.99-3.17 (m, 2 H) 2.56-2.73 (m, 2 H) 2.41 (s, 3 H) N 115

8-hydroxy-N,7- dimethyl-N-[(1R)-1- phenylethyl]quinoline- 5-sulfonamideMS (ES+) m/z 357.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm: 10.72-10.92(m, 1 H) 8.98 (dd, J = 4.04, 1.52 Hz, 1 H) 8.90 (dd, J = 8.84, 1.52 Hz,1 H) 8.11 (s, 1 H) 7.73 (dd, J = 8.59, 4.04 Hz, 1 H) 7.16-7.34 (m, 4 H)5.21 (d, J = 7.07 Hz, 1 H) 2.52 (d, J = 2.53 Hz, 3 H) 2.41 (s, 3 H)1.23-1.30 (m, 3 H). N 116

5-[(3R,4R)-3,4- difluoropyrrolidin-1- yl]sulfonyl-7-methyl-quinolin-8-ol MS (ES+) m/z 329.0 [M + H]⁺ ¹H NMR (400 MHz,Chloroform-d) δ ppm: 8.98- 9.14 (m, 2 H) 8.18 (d, J = 6.57 Hz, 1 H)7.54-7.68 (m, 1 H) 5.14-5.25 (m, 1 H) 5.02- 5.13 (m, 1 H) 3.56-3.88 (m,4 H) 2.59 (d, J = 2.53 Hz, 3H) N 117

7-chloro-8-hydroxy- N-methyl-N-[(1R)- 1- phenylethyl]quinoline-5-sulfonamide MS (ES+) m/z 377.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δppm: 9.05 (dd, J = 4.17, 1.39 Hz, 1 H) 8.93 (dd, J = 8.84, 1.52 Hz, 1 H)8.17 (s, 1 H) 7.83 (dd, J = 8.84, 4.04 Hz, 1 H) 7.19-7.35 (m, 5 H)5.20-5.31 (m, 1 H) 2.56 (s, 3 H) 1.29 (d, J = 7.07 Hz, 3H) O 118

7-chloro-5-[(2S)-2- methylpyrrolidin-1- yl]sulfonyl-quinolin- 8-ol MS(ES+) m/z 327.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm: 9.02-9.08 (m,2 H) 8.12 (s, 1 H) 7.84 (dd, J = 8.72, 4.17 Hz, 1 H) 3.82 (td, J = 6.88,3.92 Hz, 1 H) 3.26-3.36 (m, 1 H) 3.17 (dt, J = 9.92, 7.17 Hz, 1 H)1.66-1.88 (m, 2 H) 1.56 (dd, J = 6.95, 4.93 Hz, 1 H) 1.47 (dd, J =10.11, 6.06 Hz, 1 H) 1.15 (d, J = 6.32 Hz, 3 H) O 119

7-chloro-5-[(2R)-2- methylpyrrolidin-1- yl]sulfonyl-quinolin- 8-ol MS(ES+) m/z 327.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ ppm: 9.02-9.08 (m,2 H) 8.12 (s, 1 H) 7.84 (dd, J = 8.72, 4.17 Hz, 1 H) 3.82 (td, J = 6.88,3.92 Hz, 1 H) 3.26-3.36 (m, 1 H) 3.17 (dt, J = 9.92, 7.17 Hz, 1 H)1.66-1.88 (m, 2 H) 1.56 (dd, J = 6.95, 4.93 Hz, 1 H) 1.47 (dd, J =10.11, 6.06 Hz, 1 H) 1.15 (d, J = 6.32 Hz, 3 H) O 120

7-bromo-8-hydroxy- N-methyl-N-[(1R)- 1- phenylethyl]quinoline-5-sulfonamide MS (ES+) m/z 422.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δppm: 8.99-9.10 (m, 1 H) 8.86- 8.96 (m, 1 H) 8.27 (s, 1 H) 7.85 (dd, J =8.72, 4.17 Hz, 1 H) 7.13- 7.37 (m, 5 H) 5.25 (d, J = 6.82 Hz, 1 H)2.51-2.59 (m, 3 H) 1.30 (d, J = 6.82 Hz, 3 H) O 121

7-bromo-5-[4-[(4- fluorophenyl)methyl] piperazin-1-yl]sulfonyl-quinolin- 8-ol MS (ES+) m/z 482.0 [M + H]⁺ ¹H NMR (400 MHz,DMSO-d6) δ ppm: 9.05 (dd, J = 4.04, 1.52 Hz, 1 H) 8.96 (dd, J = 8.72,1.39 Hz, 1 H) 8.22 (s, 1 H) 7.84 (dd, J = 8.84, 4.29 Hz, 1 H) 7.43 (br.s., 2 H) 7.26 (t, J = 7.96 Hz, 2 H) 4.21 (br. s., 2 H) 3.78 (br. s., 4H) 3.06 (br. s., 4 H) O (Using NBS in step 3) 122

7-fluoro-5-[4-[(4- fluorophenyl)methyl] piperazin-1- yl]sulfonyl-quinolin-8-ol MS (ES+) m/z 420.0 [M + H]⁺. ¹H NMR (400 MHz, DMSO- d6) δppm: 9.05 (d, J = 4.29 Hz, 1 H) 8.97 (d, J = 7.07 Hz, 1 H) 8.15 (d, J =10.86 Hz, 1 H) 7.78 (dd, J = 8.97, 4.17 Hz, 1 H) 7.45 (d, J = 5.31 Hz, 2H) 7.30 (t, J = 8.72 Hz, 2 H) 4.29 (br. s., 2 H) 3.84 (br. s., 2 H)3.22-3.42 (m, 2 H) 3.10 (br. s., 2 H) 2.65-2.83 (m, 2 H). P 123

7-fluoro-8-hydroxy- N-methyl-N-[(1R)- 1- phenylethyl]quinoline-5-sulfonamide MS (ES+) m/z 361.0 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d6) δppm: 9.00-9.10 (m, 1 H) 8.95 (dd, J = 8.84, 1.52 Hz, 1 H) 8.18 (d, J =10.86 Hz, 1 H) 7.78 (dd, J = 8.84, 4.04 Hz, 1 H) 7.13-7.35 (m, 5 H)5.16-5.32 (m, 1 H) 2.57 (s, 3 H) 1.27 (d, J = 6.82 Hz, 3H) P

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The invention claimed is:
 1. A method of treating a neurological orpsychiatric disorder for which inhibiting COMT provides a therapeuticeffect, or treating symptoms associated with the neurological orpsychiatric disorder, comprising administering to a subject in needthereof an effective amount of a COMT-inhibiting compound in accordancewith formula I, or a pharmaceutically acceptable salt thereof,

wherein: X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄alkyl; Z is selected from SO₂R¹ and SO₂NR²R³; R¹ is selected from C₁-C₁₀alkyl, C₃-C₁₀ cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl andheteroarylalkyl, any of which may be substituted with one or more groupsselected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl,alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀ cycloalkyl, acyl,aryl, aralkyl, heterocyclyl, heteroaryl, CON(R)₂, SO₂R, and SO₂N(R)₂,where each R is independently C₁-C₄ alkyl or (R)₂ forms a carbocyclicring; R² and R³ are independently selected from hydrogen and any of thegroups as defined for R¹, with the proviso that at least one of R² andR³ is different from hydrogen; or R² and R³ may together form a 3-10membered monocyclic, bicyclic or spirocyclic nitrogen-containing ringsystem that contains 0-3 additional heteroatoms selected from oxygen(O), nitrogen (N), and sulfur (S), and which may be further substitutedwith one or more groups selected from halogen, C≡N, CF₃, OH, C₁-C₄ alkylor C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino, C₁-C₄alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl, aralkyl,heterocyclyl, heteroaryl and heteroarylalkyl; with the proviso that whenX is hydrogen and Z is SO₂R¹, R¹ is not C₄ alkyl, C₈ alkyl,tetrahydropyran or propylcyclopropane; or when X is H and Z is SO₂NR²R³,R² and R³ do not together form a 1-piperidinyl ring substituted with aα-methyl group; or when X is C₁ and Z is SO₂R¹, R¹ is not C₃ alkyl, C₄alkyl or C₅-C₆ cycloalkyl; or when X is C₁ and Z is SO₂NR²R³, R² and R³do not together form an unsubstituted, 1-pyrrolidinyl ring.
 2. Themethod of claim 1, wherein the disorder is Parkinson's disease.
 3. Themethod of claim 1, wherein the disorder is selected from majordepression, a depressive phase of bipolar disorder and age-associatedcognitive symptoms.
 4. The method of claim 1, wherein the disorder isschizophrenia.
 5. The method of claim 1, wherein X is either ofhydrogen, halogen or methyl.
 6. The method of claim 1, wherein Z isSO₂NR²R³ with R² and R³ may together form a 3-10 membered monocyclic,bicyclic or spirocyclic nitrogen-containing ring system that contains0-3 additional heteroatoms selected from oxygen (O), nitrogen (N), andsulfur (S), and which may be further substituted with one or more groupsselected from halogen, C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl,C₁-C₄ alkoxy, arylalkoxy, nitro, amino, C₁-C₄ alkoxycarbonyl, acyl,C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl, aralkyl, heterocyclyl, andheteroaryl.
 7. The method of claim 1, wherein Z is SO₂R¹ and R¹ isselected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, phenyl, naphthyl,aralkyl, C-attached piperidinyl, C-attached 1H-benzimidazolyl,C-attached tetrahydro-2H-pyranyl and pyridinyl, any of which may besubstituted with one or more groups selected from halogen, CF₃, C₁-C₄alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, substituted or unsubstitutedphenyl, substituted or unsubstituted pyridinyl, substituted orunsubstituted quinolinyl, substituted or unsubstituted 1H-indazolyl,substituted or unsubstituted aralkyl, and acyl.
 8. The method of claim1, wherein the compound is selected from the group consisting of:5-tosylquinolin-8-ol; 5-(4-fluorophenyl)sulfonylquinolin-8-ol;5-(3,4-dimethylphenyl)sulfonylquinolin-8-ol;5-(3,5-dimethylphenyl)sulfonylquinolin-8-ol;5-(4-tert-butylphenyl)sulfonylquinolin-8-ol;5-(3-phenylphenyl)sulfonylquinolin-8-ol;5-(m-tolylsulfonyl)quinolin-8-ol;5-(3,5-dichlorophenyl)sulfonylquinolin-8-ol;5-(4-chlorophenyl)sulfonylquinolin-8-ol;5-(2,4-dimethylphenyl)sulfonylquinolin-8-ol;5-[4-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;5-(2-naphthylsulfonyl)quinolin-8-ol;5-[3-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;5-(3-chlorophenyl)sulfonylquinolin-8-ol;5-(3,4-dichlorophenyl)sulfonylquinolin-8-ol;5-(2-pyridylsulfonyl)quinolin-8-ol; 5-(4-pyridylsulfonyl)quinolin-8-ol;5-(4-methoxyphenyl)sulfonylquinolin-8-ol;5-(3-pyridylsulfonyl)quinolin-8-ol;5-(4-fluoro-2-methyl-phenyl)sulfonylquinolin-8-ol;5-[2-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;5-(benzenesulfonyl)quinolin-8-ol; 5-[3-(4-pyridyl)phenyl]sulfonylquinolin-8-ol;5-[3-(3-chloro-4-fluoro-phenyl)phenyl]sulfonylquinolin-8-ol;5-[3-(5-quinolyl)phenyl] sulfonylquinolin-8-ol;5-[3-(1H-indazol-4-yl)phenyl] sulfonylquinolin-8-ol;5-[(3-methyl-4-pyridyl)sulfonyl]quinolin-8-ol;5-[1-[(2-chlorophenyl)methyl]benzimidazol-4-yl]sulfonylquinolin-8-ol;5-[2-(p-tolyl)ethylsulfonyl]quinolin-8-ol;5-cyclohexylsulfonylquinolin-8-ol; 5-cyclopentylsulfonylquinolin-8-ol;5-(p-tolylmethylsulfonyl)quinolin-8-ol; 5-ethylsulfonylquinolin-8-ol;5-(4-piperidyl sulfonyl)quinolin-8-ol;5-[[1-[(4-fluorophenyl)methyl]-4-piperidyl]sulfonyl]quinolin-8-ol;5-[[1-[(2,3-dichlorophenyl)methyl]-4-piperidyl] sulfonyl]quinolin-8-ol;5-[[1-(2,3-dimethylphenyl)-4-piperidyl] sulfonyl] quinolin-8-ol;5-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)quinolin-8-ol;5-(4-phenylpiperazin-1-yl)sulfonylquinolin-8-ol;8-hydroxy-N-[(3-methoxyphenyl)methyl]-N-methyl-quinoline-5-sulfonamide;5-(4-benzylpiperazin-1-yl)sulfonylquinolin-8-ol;8-hydroxy-N-(4-methylbenzyl)quinoline-5-sulfonamide;N-benzyl-8-hydroxy-N-methylquinoline-5-sulfonamide;8-hydroxy-N-(4-methylphenyl)-N-methylquinoline-5-sulfonamide;5-isoindolin-2-ylsulfonylquinolin-8-ol;8-hydroxy-N-methyl-N-phenethyl-quinoline-5-sulfonamide;N-[(4-fluorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;8-hydroxy-N-methyl-N-[(1 S)-1-phenylethyl] quinoline-5-sulfonamide;N-[(2-fluorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;N-[(3-chlorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;8-hydroxy-N-methyl-N-(3-pyridylmethyl)quinoline-5-sulfonamide;8-hydroxy-N-methyl-N-(2-naphthylmethyl)quinoline-5-sulfonamide;N-benzyl-N-ethyl-8-hydroxy-quinoline-5-sulfonamide;N-benzyl-N-(2-dimethylaminoethyl)-8-hydroxy-quinoline-5-sulfonamide;5-(2-phenylpyrrolidin-1-yl)sulfonylquinolin-8-ol;5-pyrrolidin-1-ylsulfonylquinolin-8-ol;5-(4-methylpiperazin-1-yl)sulfonylquinolin-8-ol;5-[(2-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;5-(3-(4-fluorophenyl)pyrrolidin-1-yl)sulfonylquinolin-8-ol;5-(piperidin-1-yl)sulfonylquinolin-8-ol;5-(4-morpholin-1-yl)sulfonylquinolin-8-ol;N-[(4-(trifluoromethyl)phenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;N-ethyl-8-hydroxy-N-(4-pyridylmethyl)quinoline-5-sulfonamide;5-(6,8-dihydro-5H-1,7-naphthyridin-7-ylsulfonyl)quinolin-8-ol;N,N-diethyl-8-hydroxy-quinoline-5-sulfonamide;5-[4-(5-chloro-2-pyridyl)piperazin-1-yl] sulfonylquinolin-8-ol;5-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]sulfonylquinolin-8-ol;5-[2-(o-tolyl)pyrrolidin-1-yl] sulfonylquinolin-8-ol;5-[2-(3-pyridyl)pyrrolidin-1-yl] sulfonylquinolin-8-ol;5-[(4-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;5-[2-(4-fluorophenyl)pyrrolidin-1-yl] sulfonylquinolin-8-ol;5-(2-benzylpyrrolidin-1-yl)sulfonylquinolin-8-ol;5-(2-cyclohexylpyrrolidin-1-yl)sulfonylquinolin-8-ol;5-[2-(4-methoxyphenyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;5-(2-isopropylpyrrolidin-1-yl)sulfonylquinolin-8-ol;5-[2-(4-pyridyl)pyrrolidin-1-yl] sulfonylquinolin-8-ol;5-[2-(2-pyridyl)pyrrolidin-1-yl] sulfonylquinolin-8-ol;5-[2-[2-(trifluoromethyl)phenyl]pyrrolidin-1-yl]sulfonylquinolin-8-ol;5-(2-isobutylpyrrolidin-1-yl)sulfonylquinolin-8-ol;5-[(4-hydroxy-4-phenyl-1-piperidyl)sulfonyl] quinolin-8-ol;5-[(4-benzyl-1-piperidyl)sulfonyl]quinolin-8-ol;[1-[(8-hydroxy-5-quinolyl)sulfonyl]-4-piperidyl]-phenyl-methanone;1-[1-[(8-hydroxy-5-quinolyl)sulfonyl]-4-phenyl-4-piperidyl]ethanone;8-[(8-hydroxy-5-quinolyl)sulfonyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;methyl 4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazine-1-carboxylate;5-[4-(3-methoxypropyl)piperazin-1-yl]sulfonylquinolin-8-ol;2-[4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazin-1-yl]benzonitrile;5-(3-azabicyclo[3.2.2]nonan-3-ylsulfonyl)quinolin-8-ol;5-[4-(2-phenylphenyl)piperazin-1-yl] sulfonylquinolin-8-ol;5-[4-(2,5-dimethylphenyl)piperazin-1-yl] sulfonylquinolin-8-ol;5-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]sulfonylquinolin-8-ol;5-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]sulfonylquinolin-8-ol;5-[4-(4-fluorophenyl)piperazin-1-yl] sulfonylquinolin-8-ol;5-[4-(2,3-dichlorophenyl)piperazin-1-yl] sulfonylquinolin-8-ol;5-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl] sulfonylquinolin-8-ol;5-[3-[4-(trifluoromethoxy)phenoxy]azetidin-1-yl] sulfonylquinolin-8-ol;5-[4-(2,3-dimethylphenyl)piperazin-1-yl] sulfonylquinolin-8-ol;5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl] sulfonylquinolin-8-ol;5-[(3-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol; tert-butyl4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazine-1-carboxylate;5-piperazin-1-ylsulfonylquinolin-8-ol; tert-butyl4-[(8-hydroxy-5-quinolyl)sulfonyl]-3-methyl-piperazine-1-carboxylate;5-(2-methylpiperazin-1-yl)sulfonylquinolin-8-ol;7-iodo-5-(p-tolylsulfonyl)quinolin-8-ol;7-bromo-5-(p-tolylsulfonyl)quinolin-8-ol;7-chloro-5-(p-tolylsulfonyl)quinolin-8-ol;7-fluoro-5-(p-tolylsulfonyl)quinolin-8-ol;7-methyl-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol;7-chloro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol;7-fluoro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol;5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-7-methyl-quinolin-8-ol;8-hydroxy-N,7-dimethyl-N-[(1R)-1-phenylethyl] quinoline-5-sulfonamide;5-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]sulfonyl-7-methyl-quinolin-8-ol;7-chloro-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;7-chloro-5-[(2 S)-2-methylpyrrolidin-1-yl] sulfonyl-quinolin-8-ol;7-chloro-5-[(2R)-2-methylpyrrolidin-1-yl] sulfonyl-quinolin-8-ol;7-bromo-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;7-bromo-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol;7-fluoro-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol;7-fluoro-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;5-(p-tolylsulfonyl)-7-(trifluoromethyl)quinolin-8-ol;5-cyclopentylsulfonyl-7-(trifluoromethyl)quinolin-8-ol;5-[[1-(4-fluorophenyl)-4-piperidyl]sulfonyl]quinolin-8-ol; and5-[(2-methylpyrrolidin-1-yl)sulfonyl] quinolin-8-ol.
 9. A method oftreating a neurological or psychiatric disorder for which inhibitingCOMT provides a therapeutic effect, or treating symptoms associated withthe neurological or psychiatric disorder, comprising administering to asubject in need thereof an effective amount of a COMT-inhibitingcompound in accordance with formula I, or a pharmaceutically acceptablesalt thereof:

wherein: X is halogen or CF₃; Z is SO₂NR²R³; and R² and R³ together forma 3-10 membered monocyclic nitrogen-containing ring system that may beoptionally substituted with one or more groups selected from halogen,C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy,nitro, amino, C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃,aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl.
 10. Themethod according to claim 9, wherein: R² and R³ together form apyrrolidine ring system that may be optionally substituted with one ormore groups selected from halogen, C≡N, CF₃, OH, and C₁-C₄ alkyl. 11.The method according to claim 9, wherein: R² and R³ are independentlyselected from any of the groups as defined for R¹; or R² and R³ maytogether form a 3-10 membered monocyclic, bicyclic or spirocyclicnitrogen-containing ring system that contains 0-3 additional heteroatomsselected from oxygen (O), nitrogen (N), and sulfur (S), and which may befurther substituted with one or more groups selected from halogen, C≡N,CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro,amino, C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl,aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl.
 12. The methodaccording to claim 9, wherein the halogen is fluorine.
 13. The methodaccording to claim 12, wherein the compound is selected from the groupconsisting of: 7-fluoro-5-(p-tolylsulfonyl)quinolin-8-ol;7-fluoro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol;7-fluoro-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol; and7-fluoro-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide.
 14. The method according to claim 1, wherein R²and R³ together form a 3-10 membered monocyclic, bicyclic or spirocyclicnitrogen-containing ring system that contains 0-1 additional heteroatomsselected from oxygen (O), nitrogen (N), and sulfur (S), and which may befurther substituted with one or more groups selected from halogen, C≡N,CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro,amino, C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl,aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl.
 15. The methodaccording to claim 1, wherein the disorder is selected from attentiondeficit disorder, attention deficit/hyperactivity disorder, substancedependency, and impulse control disorders.
 16. The method according toclaim 1, wherein the compound of formula I is administered incombination with L-DOPA and the disorder is Parkinson's disease.
 17. Amethod of reducing the risk of a neurological or psychiatric disorderfor which inhibiting COMT provides a therapeutic effect comprisingadministering to a subject in need thereof an effective amount of aCOMT-inhibiting compound in accordance with formula I, or apharmaceutically acceptable salt thereof,

wherein: X is selected from hydrogen, halogen, C≡N, CF₃, and C₁-C₄alkyl; Z is selected from SO₂R¹ and SO₂NR²R³; R¹ is selected from C₁-C₁₀alkyl, C₃-C₁₀ cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl andheteroarylalkyl, any of which may be substituted with one or more groupsselected from halogen, C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl,alkoxy, nitro, amino, C₁-C₄ alkylamino, oxo, C₃-C₁₀ cycloalkyl, acyl,aryl, aralkyl, heterocyclyl, heteroaryl, CON(R)₂, SO₂R, and SO₂N(R)₂,where each R is independently C₁-C₄ alkyl or (R)₂ forms a carbocyclicring; R² and R³ are independently selected from hydrogen and any of thegroups as defined for R¹, with the proviso that at least one of R² andR³ is different from hydrogen; or R² and R³ may together form a 3-10membered monocyclic, bicyclic or spirocyclic nitrogen-containing ringsystem that contains 0-3 additional heteroatoms selected from oxygen(O), nitrogen (N), and sulfur (S), and which may be further substitutedwith one or more groups selected from halogen, C≡N, CF₃, OH, C₁-C₄ alkylor C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy, nitro, amino, C₁-C₄alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃, aryl, aralkyl,heterocyclyl, heteroaryl and heteroarylalkyl; with the proviso that whenX is hydrogen and Z is SO₂R¹, R¹ is not C₄ alkyl, C₈ alkyl,tetrahydropyran or propylcyclopropane; or when X is H and Z is SO₂NR²R³,R² and R³ do not together form a 1-piperidinyl ring substituted with aα-methyl group; or when X is C₁ and Z is SO₂R¹, R¹ is not C₃ alkyl, C₄alkyl or C₅-C₆ cycloalkyl; or when X is C₁ and Z is SO₂NR²R³, R² and R³do not together form an unsubstituted, 1-pyrrolidinyl ring.
 18. Themethod of claim 17, wherein the neurological or psychiatric disorder isschizophrenia, depression, or a depressive phase of bipolar disorder.19. A method of reducing the risk of a neurological or psychiatricdisorder for which inhibiting COMT provides a therapeutic effect, themethod comprising administering to a subject in need thereof aneffective amount of a COMT-inhibiting compound in accordance withformula I, or a pharmaceutically acceptable salt thereof:

wherein: X is halogen or CF₃; Z is SO₂NR²R³; and R² and R³ together forma 3-10 membered monocyclic nitrogen-containing ring system that may beoptionally substituted with one or more groups selected from halogen,C≡N, CF₃, OH, C₁-C₄ alkyl or C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, alkoxy,nitro, amino, C₁-C₄ alkoxycarbonyl, acyl, C₁-C₄ alkylamino, oxo, SO₂CH₃,aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl.
 20. Themethod of claim 19, wherein the neurological or psychiatric disorder isschizophrenia, depression, or a depressive phase of bipolar disorder.